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Castro-Rodríguez LI, Velez-delValle C, Hernández-Mosqueira CP, Kuri-Harcuch W. Spot-14 and its paralog Spot-14R regulate expression of metabolic and thermogenic pathway genes in murine brown and beige adipocytes. FEBS Lett 2025. [PMID: 40317955 DOI: 10.1002/1873-3468.70052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 01/24/2025] [Accepted: 03/07/2025] [Indexed: 05/07/2025]
Abstract
Spot 14 (S14), encoded by Thrsp, is a thyroid hormone-responsive transcriptional activator that regulates lipogenesis, though its mechanisms remain unclear. We aimed to study the role of S14 on gene expression in adipocytes. We analyzed Thrsp and its paralog Mid1ip1 in brown (EB5), beige (EB7), and white (F442A) adipocytes. Thrsp expression was higher in EB5 and EB7 than in F442A and increased with thyroid hormone T3 in EB5 and EB7 but decreased in F442A. Mid1ip1 expression rose moderately in EB5 and EB7, influencing lipid metabolism genes. Silencing Thrsp upregulated Mid1ip1 in EB7 and reduced thermogenic gene expression in EB5 and EB7. These findings underscore the roles of Thrsp and Mid1ip1 in metabolic and thermogenic pathways, highlighting the responsiveness of S14 to thyroid hormones and nutrient signals. Impact statement This study reveals that Thyroid Hormone-Induced Protein 8 (THRSP), also known as Spot-14, and its paralog Spot-14R, regulate metabolic and thermogenic gene expression differently in brown and beige adipocytes. These findings provide insights into adipocyte metabolism, offering potential targets for obesity and metabolic disorder treatments.
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Affiliation(s)
| | - Cristina Velez-delValle
- Department of Cell Biology, Center for Research and Advanced Studies (Cinvestav), Mexico City, Mexico
| | | | - Walid Kuri-Harcuch
- Department of Cell Biology, Center for Research and Advanced Studies (Cinvestav), Mexico City, Mexico
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2
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Li Y, Li RY, Zhu JY, Chen M, Mu WJ, Luo HY, Li S, Yan LJ, Yin MT, Li X, Chen HM, Guo L. Maternal exercise prevents metabolic disorders in offspring mice through SERPINA3C. Nat Metab 2025; 7:401-420. [PMID: 39891022 DOI: 10.1038/s42255-024-01213-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 12/17/2024] [Indexed: 02/03/2025]
Abstract
Maternal exercise can improve the metabolic health of the offspring. However, the molecular mechanisms underlying the beneficial effects of maternal exercise on the offspring remain unclear. Here, we show that maternal exercise during pregnancy alleviates high-fat diet (HFD)-induced adipose inflammation and glucose intolerance in offspring mice, accompanied by upregulation of the adipokine serine protease inhibitor A3C (SERPINA3C) both in maternal adipose tissues and the fetal circulation. Adipose SERPINA3C knockdown impairs, but its overexpression in dams mimics, maternal exercise-mediated metabolic benefits in HFD-fed offspring. Maternal SERPINA3C is transported into the fetal circulation and promotes Krüppel-like factor 4 (Klf4) gene promoter demethylation in fetal preadipocytes to increase KLF4 expression, which inhibits adipose inflammation in HFD-fed offspring mice. The SERPINA3C-cathepsin G-integrin β1 axis activates phosphatidylinositol 3-kinase signalling in preadipocytes. This promotes nuclear translocation of the p110β subunit to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the nucleus. O-linked β-N-acetylglucosamine (O-GlcNAc) transferase then binds to PIP3 to promote ten-eleven translocation methylcytosine dioxygenase 1 (TET1) O-GlcNAcylation, thereby enhancing TET1 activity to facilitate Klf4 gene promoter demethylation. These results provide mechanistic insights into maternal exercise-mediated improvement of offspring metabolism.
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Affiliation(s)
- Yang Li
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Ruo-Ying Li
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Jie-Ying Zhu
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Min Chen
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Wang-Jing Mu
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Hong-Yang Luo
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Shan Li
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Lin-Jing Yan
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Meng-Ting Yin
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Xin Li
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Hu-Min Chen
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Liang Guo
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China.
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China.
- Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai, China.
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3
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Zhang H, Lu W, Tang H, Chen A, Gao X, Zhu C, Zhang J. Novel Insight of N6-Methyladenosine in Cardiovascular System. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:222. [PMID: 40005339 PMCID: PMC11857502 DOI: 10.3390/medicina61020222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/19/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025]
Abstract
N6-methyladenosine (m6A) is the most common and abundant internal co-transcriptional modification in eukaryotic RNAs. This modification is catalyzed by m6A methyltransferases, known as "writers", including METTL3/14 and WTAP, and removed by demethylases, or "erasers", such as FTO and ALKBH5. It is recognized by m6A-binding proteins, or "readers", such as YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, and HNRNPA2B1. Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Recent studies indicate that m6A RNA modification plays a critical role in both the physiological and pathological processes involved in the initiation and progression of CVDs. In this review, we will explore how m6A RNA methylation impacts both the normal and disease states of the cardiovascular system. Our focus will be on recent advancements in understanding the biological functions, molecular mechanisms, and regulatory factors of m6A RNA methylation, along with its downstream target genes in various CVDs, such as atherosclerosis, ischemic diseases, metabolic disorders, and heart failure. We propose that the m6A RNA methylation pathway holds promise as a potential therapeutic target in cardiovascular disease.
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Affiliation(s)
- Huan Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Wei Lu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Haoyue Tang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Aiqun Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Xiaofei Gao
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Congfei Zhu
- Department of Cardiology, Lianshui County People’s Hospital, Affiliated Hospital of Kangda College, Nanjing Medical University, Huaian 223400, China
| | - Junjie Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
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4
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Fan S, Zhao M, Wang K, Deng Y, Yu X, Ma K, Zhang Y, Xiao H. Exercise training attenuates cardiac dysfunction induced by excessive sympathetic activation through an AMPK-KLF4-FMO2 axis. J Mol Cell Cardiol 2024; 197:136-149. [PMID: 39491669 DOI: 10.1016/j.yjmcc.2024.10.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 10/07/2024] [Accepted: 10/28/2024] [Indexed: 11/05/2024]
Abstract
Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide and are associated with an overactivated sympathetic system. Although exercise training has shown promise in mitigating sympathetic stress-induced cardiac remodeling, the precise mechanisms remain elusive. Here, we demonstrate that exercise significantly upregulates cardiac flavin-containing monooxygenase 2 (FMO2) expression. Notably, we find that exercise training effectively counteracts sympathetic overactivation-induced cardiac dysfunction and fibrosis by enhancing FMO2 expression via adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Functional investigations employing FMO2 knockdown with adeno-associated virus 9 (AAV9) underscore the necessity for FMO2 expression to protect the heart during exercise in vivo. Furthermore, we identify the krüppel-like factor 4 (KLF4) as a transcriptional mediator of FMO2 that is crucial for the mechanism through which AMPK activation protects against sympathetic overactivation-induced cardiac dysfunction and fibrosis. Taken together, our study reveals a cardioprotective mechanism for exercise training through an AMPK-KLF4-FMO2 signaling pathway that underscores how exercise alleviates cardiac dysfunction induced by excessive sympathetic activation.
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Affiliation(s)
- Shiyu Fan
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi 832003, China
| | - Mingming Zhao
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China
| | - Kang Wang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China
| | - Yawen Deng
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China
| | - Xiaoyue Yu
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China
| | - Ketao Ma
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi 832003, China
| | - Youyi Zhang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China.
| | - Han Xiao
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi 832003, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China.
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5
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Jiang Y, Wang W, Wang H, Zhang X, Kong Y, Chen YQ, Zhu S. ACSL1 positively regulates adipogenic differentiation. Biochem Biophys Res Commun 2024; 735:150865. [PMID: 39442449 DOI: 10.1016/j.bbrc.2024.150865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 10/16/2024] [Accepted: 10/19/2024] [Indexed: 10/25/2024]
Abstract
Aberrant adipogenic differentiation is strongly associated with obesity and related metabolic diseases. Elucidating the key factors driving adipogenesis is an effective strategy for identifying novel therapeutic targets for treating metabolic diseases represented by obesity. In this study, transcriptomic techniques were employed to investigate the functional genes that regulate adipogenic differentiation in OP9 cells and 3T3-L1 cells. The findings indicated a notable upregulation of Acsl1 expression throughout the adipogenic differentiation process. Knocking down Acsl1 led to a decrease in the expression of genes associated with adipogenesis and a reduction in triglyceride accumulation. Additionally, Acsl1 overexpression promoted adipocyte differentiation and adipose-specific overexpression of Acsl1 markedly aggravated steatosis induced by a high-fat diet. Mechanistically, Cyp2f2, Dusp23 and Gstm2 are the crucial genes implicated in Acsl1-induced adipogenic differentiation. The findings of this study indicate that Acsl1 promotes adipogenesis and could serve as a potential therapeutic target for treating obesity and related metabolic disorders.
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Affiliation(s)
- Yao Jiang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Wei Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China; The Second School of Clinical Medical, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hui Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Xiaoru Zhang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Yuling Kong
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Yong Q Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, China.
| | - Shenglong Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China.
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6
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Guo G, Wang W, Tu M, Zhao B, Han J, Li J, Pan Y, Zhou J, Ma W, Liu Y, Sun T, Han X, An Y. Deciphering adipose development: Function, differentiation and regulation. Dev Dyn 2024; 253:956-997. [PMID: 38516819 DOI: 10.1002/dvdy.708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/02/2024] [Accepted: 03/10/2024] [Indexed: 03/23/2024] Open
Abstract
The overdevelopment of adipose tissues, accompanied by excess lipid accumulation and energy storage, leads to adipose deposition and obesity. With the increasing incidence of obesity in recent years, obesity is becoming a major risk factor for human health, causing various relevant diseases (including hypertension, diabetes, osteoarthritis and cancers). Therefore, it is of significance to antagonize obesity to reduce the risk of obesity-related diseases. Excess lipid accumulation in adipose tissues is mediated by adipocyte hypertrophy (expansion of pre-existing adipocytes) or hyperplasia (increase of newly-formed adipocytes). It is necessary to prevent excessive accumulation of adipose tissues by controlling adipose development. Adipogenesis is exquisitely regulated by many factors in vivo and in vitro, including hormones, cytokines, gender and dietary components. The present review has concluded a comprehensive understanding of adipose development including its origin, classification, distribution, function, differentiation and molecular mechanisms underlying adipogenesis, which may provide potential therapeutic strategies for harnessing obesity without impairing adipose tissue function.
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Affiliation(s)
- Ge Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Wanli Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Mengjie Tu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Binbin Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jiayang Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jiali Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yanbing Pan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jie Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Wen Ma
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yi Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Tiantian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Xu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
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7
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Patel S, Ganbold K, Cho CH, Siddiqui J, Yildiz R, Sparman N, Sadeh S, Nguyen CM, Wang J, Whitelegge JP, Fried SK, Waki H, Villanueva CJ, Seldin MM, Sakaguchi S, Ellmeier W, Tontonoz P, Rajbhandari P. Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors. Nat Commun 2024; 15:8533. [PMID: 39358382 PMCID: PMC11447024 DOI: 10.1038/s41467-024-52917-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 09/25/2024] [Indexed: 10/04/2024] Open
Abstract
White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1's function during differentiation. These findings underscore PATZ1's regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development.
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Affiliation(s)
- Sanil Patel
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Khatanzul Ganbold
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Chung Hwan Cho
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Juwairriyyah Siddiqui
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ramazan Yildiz
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Njeri Sparman
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Shani Sadeh
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Christy M Nguyen
- Department of Biological Chemistry, University of California, Irvine, CA, 92697, USA
| | - Jiexin Wang
- Department of Pathology and Laboratory Medicine and Department of Biological Chemistry, University of California, Los Angeles, CA, 90095, USA
| | - Julian P Whitelegge
- Pasarow Mass Spectrometry Laboratory, NPI-Semel Institute, University of California, Los Angeles, CA, 90095, USA
| | - Susan K Fried
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Hironori Waki
- Department of Metabolism and Endocrinology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Claudio J Villanueva
- Molecular, Cellular, and Integrative Physiology Program, and Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, 90095, USA
| | - Marcus M Seldin
- Department of Biological Chemistry, University of California, Irvine, CA, 92697, USA
| | - Shinya Sakaguchi
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, Austria
| | - Wilfried Ellmeier
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, Austria
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine and Department of Biological Chemistry, University of California, Los Angeles, CA, 90095, USA
| | - Prashant Rajbhandari
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Disease Mechanism and Therapeutics Program, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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8
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Mo YY, Han YX, Xu SN, Jiang HL, Wu HX, Cai JM, Li L, Bu YH, Xiao F, Liang HD, Wen Y, Liu YZ, Yin YL, Zhou HD. Adipose Tissue Plasticity: A Comprehensive Definition and Multidimensional Insight. Biomolecules 2024; 14:1223. [PMID: 39456156 PMCID: PMC11505740 DOI: 10.3390/biom14101223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/28/2024] Open
Abstract
Adipose tissue is composed of adipocytes, stromal vascular fraction, nerves, surrounding immune cells, and the extracellular matrix. Under various physiological or pathological conditions, adipose tissue shifts cellular composition, lipid storage, and organelle dynamics to respond to the stress; this remodeling is called "adipose tissue plasticity". Adipose tissue plasticity includes changes in the size, species, number, lipid storage capacity, and differentiation function of adipocytes, as well as alterations in the distribution and cellular composition of adipose tissue. This plasticity has a major role in growth, obesity, organismal protection, and internal environmental homeostasis. Moreover, certain thresholds exist for this plasticity with significant individualized differences. Here, we comprehensively elaborate on the specific connotation of adipose tissue plasticity and the relationship between this plasticity and the development of many diseases. Meanwhile, we summarize possible strategies for treating obesity in response to adipose tissue plasticity, intending to provide new insights into the dynamic changes in adipose tissue and contribute new ideas to relevant clinical problems.
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Affiliation(s)
- Yu-Yao Mo
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
| | - Yu-Xin Han
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
| | - Shi-Na Xu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
| | - Hong-Li Jiang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
| | - Hui-Xuan Wu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
| | - Jun-Min Cai
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
| | - Long Li
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
| | - Yan-Hong Bu
- Department of Blood Transfusion, The Second Xiangya Hospital, Central South University, Changsha 410012, China;
| | - Fen Xiao
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
| | - Han-Dan Liang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
| | - Ying Wen
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
| | - Yu-Ze Liu
- Pediatric Cardiac Surgery Centre, Fuwai Hospital, National Centre for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China;
| | - Yu-Long Yin
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Hou-De Zhou
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (Y.-Y.M.); (Y.-X.H.); (S.-N.X.); (H.-L.J.); (H.-X.W.); (J.-M.C.); (L.L.); (F.X.); (H.-D.L.); (Y.W.)
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9
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Ma Z, Chu H, Li F, Han G, Cai Y, Yi J, Lu M, Xiang H, Kang H, Ye F, Chen S, Li H. Genome-Wide Identification, Evolution, and miRNA-22 Regulation of Kruppel-Like Factor ( KLF) Gene Family in Chicken ( Gallus gallus). Animals (Basel) 2024; 14:2594. [PMID: 39272379 PMCID: PMC11394431 DOI: 10.3390/ani14172594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/10/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
Krüppel-like factors (KLFs) are a class of fundamental transcription factors that are widely present in various eukaryotes from nematodes to humans, named after their DNA binding domain which is highly homologous to the Krüppel factor in fruit flies. To investigate the composition, organization, and evolutionary trajectory of KLF gene family members in chickens, in our study, we leveraged conserved sequences of KLF genes from representative classes across fish, amphibians, birds, and mammals as foundational sequences. Bioinformatic tools were employed to perform homology alignment on the chicken genome database, ultimately identifying the KLF family members present in chickens. The gene structure, phylogenetic analysis, conserved base sequences, physicochemical properties, collinearity analysis, and protein structure were then analyzed using bioinformatic tools. Additionally, the impact of miRNA-22, related to poultry lipid metabolism, on the expression of the KLF gene family in the liver, heart, and muscle of Qingyuan partridge chickens was explored. The results showed that: (1) compared to fish, the KLF family in birds is more closely related to mammals and amphibians; (2) KLFs within the same subgroups are likely to be derived from a common ancestral gene duplication; (3) KLF3/8/12 in the same subgroup may have some similar or overlapping functions; (4) the motif 4 of KLF5 was most likely lost during evolution; (5) KLF9 may perform a similar function in chickens and pigs; (6) there are collinear relationships between certain KLF genes, indicating that there are related biomolecular functions between these KLF genes; (7) all members of the KLF family in chickens are non-transmembrane proteins; and (8) interference and overexpression of miRNA-22 in Qingyuan partridge chickens can affect the expression levels of KLF genes in liver, heart, and muscle.
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Affiliation(s)
- Zheng Ma
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Huangbin Chu
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Fapei Li
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Guochao Han
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Yingqiu Cai
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Jianing Yi
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Mingrou Lu
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Hai Xiang
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Huimin Kang
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Fei Ye
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Siyu Chen
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
| | - Hua Li
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528225, China
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10
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Velez‐delValle C, Hernandez‐Mosqueira CP, Castro‐Rodriguez LI, Vazquez‐Sandoval A, Marsch‐Moreno M, Kuri‐Harcuch W. Gene expression and characterization of clonally derived murine embryonic brown and brite adipocytes. FEBS Open Bio 2024; 14:1503-1525. [PMID: 38972757 PMCID: PMC11492321 DOI: 10.1002/2211-5463.13861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 05/29/2024] [Accepted: 06/25/2024] [Indexed: 07/09/2024] Open
Abstract
White adipocytes store energy, while brown and brite adipocytes release heat via nonshivering thermogenesis. In this study, we characterized two murine embryonic clonal preadipocyte lines, EB5 and EB7, each displaying unique gene marker expression profiles. EB5 cells differentiate into brown adipocytes, whereas EB7 cells into brite (also known as beige) adipocytes. To draw a comprehensive comparison, we contrasted the gene expression patterns, adipogenic capacity, as well as carbohydrate and lipid metabolism of these cells to that of F442A, a well-known white preadipocyte and adipocyte model. We found that commitment to differentiation in both EB5 and EB7 cells can be induced by 3-Isobutyl-1-methylxanthine/dexamethasone (Mix/Dex) and staurosporine/dexamethasone (St/Dex) treatments. Additionally, the administration of rosiglitazone significantly enhances the brown and brite adipocyte phenotypes. Our data also reveal the involvement of a series of genes in the transcriptional cascade guiding adipogenesis, pinpointing GSK3β as a critical regulator for both EB5 and EB7 adipogenesis. In a developmental context, we observe that, akin to brown fat progenitors, brite fat progenitors make their appearance in murine development by 11-12 days of gestation or potentially earlier. This result contributes to our understanding of adipocyte lineage specification during embryonic development. In conclusion, EB5 and EB7 cell lines are valuable for research into adipocyte biology, providing insights into the differentiation and development of brown and beige adipocytes. Furthermore, they could be useful for the characterization of drugs targeting energy balance for the treatment of obesity and metabolic diseases.
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Affiliation(s)
- Cristina Velez‐delValle
- Department of Cell BiologyCenter for Research and Advanced Studies (Cinvestav)Mexico CityMexico
| | | | | | | | - Meytha Marsch‐Moreno
- Department of Cell BiologyCenter for Research and Advanced Studies (Cinvestav)Mexico CityMexico
| | - Walid Kuri‐Harcuch
- Department of Cell BiologyCenter for Research and Advanced Studies (Cinvestav)Mexico CityMexico
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11
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Alzaabi M, Khalili M, Sultana M, Al-Sayegh M. Transcriptional Dynamics and Key Regulators of Adipogenesis in Mouse Embryonic Stem Cells: Insights from Robust Rank Aggregation Analysis. Int J Mol Sci 2024; 25:9154. [PMID: 39273102 PMCID: PMC11395306 DOI: 10.3390/ijms25179154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/07/2024] [Accepted: 08/16/2024] [Indexed: 09/15/2024] Open
Abstract
Embryonic stem cells are crucial for studying developmental biology due to their self-renewal and pluripotency capabilities. This research investigates the differentiation of mouse ESCs into adipocytes, offering insights into obesity and metabolic disorders. Using a monolayer differentiation approach over 30 days, lipid accumulation and adipogenic markers, such as Cebpb, Pparg, and Fabp4, confirmed successful differentiation. RNA sequencing revealed extensive transcriptional changes, with over 15,000 differentially expressed genes linked to transcription regulation, cell cycle, and DNA repair. This study utilized Robust Rank Aggregation to identify critical regulatory genes like PPARG, CEBPA, and EP300. Network analysis further highlighted Atf5, Ccnd1, and Nr4a1 as potential key players in adipogenesis and its mature state, validated through RT-PCR. While key adipogenic factors showed plateaued expression levels, suggesting early differentiation events, this study underscores the value of ESCs in modeling adipogenesis. These findings contribute to our understanding of adipocyte differentiation and have significant implications for therapeutic strategies targeting metabolic diseases.
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Affiliation(s)
- Mouza Alzaabi
- Division of Biology, New York University Abu Dhabi, Saadiyaat Island, Abu Dhabi P.O. Box 129188, United Arab Emirates
| | - Mariam Khalili
- Division of Biology, New York University Abu Dhabi, Saadiyaat Island, Abu Dhabi P.O. Box 129188, United Arab Emirates
| | - Mehar Sultana
- Center for Genomics & Systems Biology, New York University Abu Dhabi, Saadiyaat Island, Abu Dhabi P.O. Box 129188, United Arab Emirates
| | - Mohamed Al-Sayegh
- Division of Biology, New York University Abu Dhabi, Saadiyaat Island, Abu Dhabi P.O. Box 129188, United Arab Emirates
- Center for Genomics & Systems Biology, New York University Abu Dhabi, Saadiyaat Island, Abu Dhabi P.O. Box 129188, United Arab Emirates
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12
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Röszer T. MicroRNA Profile of Mouse Adipocyte-Derived Extracellular Vesicles. Cells 2024; 13:1298. [PMID: 39120327 PMCID: PMC11311276 DOI: 10.3390/cells13151298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 07/26/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024] Open
Abstract
The post-transcriptional control of gene expression is a complex and evolving field in adipocyte biology, with the premise that the delivery of microRNA (miRNA) species to the obese adipose tissue may facilitate weight loss. Cells shed extracellular vesicles (EVs) that may deliver miRNAs as intercellular messengers. However, we know little about the miRNA profile of EVs secreted by adipocytes during postnatal development. Here, we defined the miRNA cargo of EVs secreted by mouse adipocytes in two distinct phases of development: on postnatal day 6, when adipocytes are lipolytic and thermogenic, and on postnatal day 56, when adipocytes have active lipogenesis. EVs were collected from cell culture supernatants, and their miRNA profile was defined by small RNA sequencing. The most abundant miRNA of mouse adipocyte-derived EVs was mmu-miR-148a-3p. Adipocyte EVs on postnatal day 6 were hallmarked with mmu-miR-98-5p, and some miRNAs were specific to this developmental stage, such as mmu-miR-466i-5p and 12 novel miRNAs. Adipocytes on postnatal day 56 secreted mmu-miR-365-3p, and 16 miRNAs were specific to this developmental stage. The miRNA cargo of adipocyte EVs targeted gene networks of cell proliferation, insulin signaling, interferon response, thermogenesis, and lipogenesis. We provided here a database of miRNAs secreted by developing mouse adipocytes, which may be a tool for further studies on the regulation of gene networks that control mouse adipocyte development.
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Affiliation(s)
- Tamás Röszer
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
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13
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Kim HY, Jang HJ, Muthamil S, Shin UC, Lyu JH, Kim SW, Go Y, Park SH, Lee HG, Park JH. Novel insights into regulators and functional modulators of adipogenesis. Biomed Pharmacother 2024; 177:117073. [PMID: 38981239 DOI: 10.1016/j.biopha.2024.117073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/27/2024] [Accepted: 06/29/2024] [Indexed: 07/11/2024] Open
Abstract
Adipogenesis is a process that differentiates new adipocytes from precursor cells and is tightly regulated by several factors, including many transcription factors and various post-translational modifications. Recently, new roles of adipogenesis have been suggested in various diseases. However, the molecular mechanisms and functional modulation of these adipogenic genes remain poorly understood. This review summarizes the regulatory factors and modulators of adipogenesis and discusses future research directions to identify novel mechanisms regulating adipogenesis and the effects of adipogenic regulators in pathological conditions. The master adipogenic transcriptional factors PPARγ and C/EBPα were identified along with other crucial regulatory factors such as SREBP, Kroxs, STAT5, Wnt, FOXO1, SWI/SNF, KLFs, and PARPs. These transcriptional factors regulate adipogenesis through specific mechanisms, depending on the adipogenic stage. However, further studies related to the in vivo role of newly discovered adipogenic regulators and their function in various diseases are needed to develop new potent therapeutic strategies for metabolic diseases and cancer.
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Affiliation(s)
- Hyun-Yong Kim
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea; New Drug Development Center, Osong Medical Innovation Foundation, 123, Osongsaengmyeong-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28160, Republic of Korea.
| | - Hyun-Jun Jang
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea; Research Group of Personalized Diet, Korea Food Research Institute, Wanju-gun, Jeollabuk-do 55365, Republic of Korea.
| | - Subramanian Muthamil
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea.
| | - Ung Cheol Shin
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea.
| | - Ji-Hyo Lyu
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea.
| | - Seon-Wook Kim
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea.
| | - Younghoon Go
- Korean Medicine (KM)-application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea.
| | - Seong-Hoon Park
- Genetic and Epigenetic Toxicology Research Group, Korea Institute of Toxicology, Daejeon 34141, Republic of Korea.
| | - Hee Gu Lee
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
| | - Jun Hong Park
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea; University of Science & Technology (UST), KIOM campus, Korean Convergence Medicine Major, Daejeon 34054, Republic of Korea.
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14
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Lei Z, Pan C, Li F, Wei D, Ma Y. SGK1 promotes the lipid accumulation via regulating the transcriptional activity of FOXO1 in bovine. BMC Genomics 2024; 25:737. [PMID: 39080526 PMCID: PMC11290151 DOI: 10.1186/s12864-024-10644-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/22/2024] [Indexed: 08/02/2024] Open
Abstract
OBJECTIVES Serum/glucocorticoid-inducible kinase 1 (SGK1) gene encodes a serine/threonine protein kinase that plays an essential role in cellular stress response and regulation of multiple metabolic processes. However, its role in bovine adipogenesis remains unknown. In this study, we aimed to clarify the role of SGK1 in bovine lipid accumulation and improvement of meat quality. METHODS Preadipocytes were induced to differentiation to detect the temporal expression pattern of SGK1. Heart, liver, lung, spleen, kidney, muscle and fat tissues were collected to detect its tissue expression profile. Recombinant adenovirus and the lentivirus were packaged for overexpression and knockdown. Oil Red O staining, quantitative real-time PCR, Western blot analysis, Yeast two-hybrid assay, luciferase assay and RNA-seq were performed to study the regulatory mechanism of SGK1. RESULTS SGK1 showed significantly higher expression in adipose and significantly induced expression in differentiated adipocytes. Furthermore, overexpression of SGK1 greatly promoted adipogenesis and inhibited proliferation, which could be shown by the remarkable increasement of lipid droplet, and the expression levels of adipogenic marker genes and cell cycle-related genes. Inversely, its knockdown inhibited adipogenesis and facilitated proliferation. Mechanistically, SGK1 regulates the phosphorylation and expression of two critical proteins of FoxO family, FOXO1/FOXO3. Importantly, SGK1 attenuates the transcriptional repression role of FOXO1 for PPARγ via phosphorylating the site S256, then promoting the bovine fat deposition. CONCLUSIONS SGK1 is a required epigenetic regulatory factor for bovine preadipocyte proliferation and differentiation, which contributes to a better understanding of fat deposition and meat quality improvement in cattle.
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Affiliation(s)
- Zhaoxiong Lei
- College of Animal Science and Technology, Ningxia University, Yinchuan, 750021, China
| | - Cuili Pan
- College of Animal Science and Technology, Ningxia University, Yinchuan, 750021, China
| | - Fen Li
- College of Animal Science and Technology, Ningxia University, Yinchuan, 750021, China
| | - Dawei Wei
- College of Animal Science and Technology, Ningxia University, Yinchuan, 750021, China.
| | - Yun Ma
- College of Animal Science and Technology, Ningxia University, Yinchuan, 750021, China.
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15
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Liu S, Xiao M, Jin J, Zhan X, Li X, Ren Y, Yu X, Liu T, Yi Y, Liang R, Peng J. Zishen Qingre Lishi Huayu recipe promotes proliferation and inhibits apoptosis of GCs of PCOS via KLF4-C/EBPβ pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 328:118027. [PMID: 38537844 DOI: 10.1016/j.jep.2024.118027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/29/2024] [Accepted: 03/07/2024] [Indexed: 04/07/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Zishen Qingre Lishi Huayu recipe (ZQLHR) is a herbal recipe created on the basis on the theory of traditional Chinese medicine and clinical practice, and is mainly used in the treatment of polycystic ovary syndrome (PCOS). However, the underlying mechanism for this fact has not been clearly elucidated. AIM OF THE STUDY To verify whether ZQLHR regulates granulosa cells (GCs) proliferation and apoptosis through the Krüppel-like factor 4 (KLF4) - CCATT enhancer-binding proteinβ (C/EBPβ) pathway, and to provide in vitro molecular mechanism supporting for the effects of ZQLHR to enhance follicular development and treat patients with PCOS. MATERIALS AND METHODS Based on previous experiments, we performed the following experiments. Firstly, we treated KGN cells (a steroidogenic human granulosa-like tumor cell line) for 48 h using different concentrations of ZQLHR in order to observe apoptosis in each group. Secondly, the mRNA and protein expression levels of KLF4 and C/EBPβ in KGN cells after administrated with ZQLHR were examined by quantitative real-time PCR(q-PCR) and Western blot assay. Thirdly, after knocking down KLF4 and C/EBPβ using siRNAs, the relationship between KLF4 and C/EBPβ in KGN cells was detected. Further, cell counting kit-8 assay, colony formation assay and flow cytometry were used to verify whether ZQLHR promotes proliferation and facilitates apoptosis in KGN cells through the KLF4-C/EBPβ pathway. Finally, q-PCR and Western blot were used to test whether ZQLHR mediated proliferation and apoptosis-related factors such as B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (BAX), proliferating cell nuclear antigen (PCNA) and cleaved caspase-3 to affect the proliferation and apoptosis of KGN cells through the KLF4-C/EBPβ pathway. CONCLUSIONS ZQLHR, containing 0.2% by volume, administered to KGN cells resulted in the lowest rate of apoptosis. The expression levels of KLF4 and C/EBPβ were increased in KGN cells following ZQLHR treatment. Additionally, ZQLHR promoted proliferation and inhibited apoptosis of KGN cells by modulating proliferation and apoptosis-related factors via the KLF4-C/EBPβ pathway. Furthermore, we confirmed that KLF4 and C/EBPβ regulate each other in KGN cells. These findings indicate that ZQLHR enhances the proliferation of GCs and suppresses their apoptosis, which constitutes a therapeutic mechanism for treating patients with PCOS.
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Affiliation(s)
- Shuzhen Liu
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China
| | - Min Xiao
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China
| | - Jing Jin
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China
| | - Xiaoxuan Zhan
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China
| | - Xin Li
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China
| | - Yunying Ren
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China
| | - Xingxing Yu
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China
| | - Tingting Liu
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China
| | - Yao Yi
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China; Institute of Obstetrics and Gynecology, Jiangxi University of Chinese Medicine, Nanchang, 330000, China
| | - Ruining Liang
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China; The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, 330000, China; Institute of Obstetrics and Gynecology, Jiangxi University of Chinese Medicine, Nanchang, 330000, China.
| | - Jiahua Peng
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China; Institute of Obstetrics and Gynecology, Jiangxi University of Chinese Medicine, Nanchang, 330000, China.
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16
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Wu HY, Ji ZH, Xie WY, Guo HX, Zheng Y, Gao W, Yuan B. KLF4 promotes milk fat synthesis by regulating the PI3K-AKT-mTOR pathway and targeting FASN activation in bovine mammary epithelial cells. iScience 2024; 27:109850. [PMID: 38779481 PMCID: PMC11108978 DOI: 10.1016/j.isci.2024.109850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/18/2024] [Accepted: 04/26/2024] [Indexed: 05/25/2024] Open
Abstract
Milk fat is an important indicator for evaluating the quality of cow's milk. In this study, we used bovine mammary epithelial cells (BMECs) to investigate the role and molecular mechanism of KLF4 in the regulation of milk fat synthesis. The results showed that KLF4 was more highly expressed in mammary tissues of high-fat cows compared with low-fat cows. KLF4 positively regulated the expression of genes related to milk fat synthesis in BMECs, increasing intracellular triglycerides content, and KLF4 promoted milk fat synthesis by activating the PI3K-AKT-mTOR signaling pathway. Furthermore, the results of animal experiments also confirmed that knockdown of KLF4 inhibited milk fat synthesis. In addition, yeast one-hybrid assays and dual-luciferase reporter gene assays confirmed that KLF4 directly targets and binds to the fatty acid synthase (FASN) promoter region to promote FASN transcription. These results demonstrate that KLF4 is a key transcription factor for milk fat synthesis in BMECs.
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Affiliation(s)
- Hong-Yu Wu
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin 130062, China
- Jilin Academy of Agricultural Sciences, Jilin 132101, China
| | - Zhong-Hao Ji
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin 130062, China
- Department of Basic Medicine, Changzhi Medical College, Changzhi 046000, Shanxi, China
| | - Wen-Yin Xie
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin 130062, China
| | - Hai-Xiang Guo
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin 130062, China
| | - Yi Zheng
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin 130062, China
| | - Wei Gao
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin 130062, China
| | - Bao Yuan
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin 130062, China
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17
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Wang H, Guo S, Gao H, Ding J, Li H, Kong X, Zhang S, He M, Feng Y, Wu W, Xu K, Chen Y, Zhang H, Liu T, Kong X. Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communication. J Clin Invest 2024; 134:e178303. [PMID: 38889010 PMCID: PMC11324308 DOI: 10.1172/jci178303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 06/17/2024] [Indexed: 06/20/2024] Open
Abstract
Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTNΔUCP1) and found that the mice gained more weight than did controls when fed a high-fat diet, with progressive hepatosteatosis and impaired skeletal muscle activity. RNA-Seq analysis indicated signatures of mitochondrial dysfunction and inflammation in the MSTN-ablated BAT. Further studies demonstrated that Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, whereas fibroblast growth factor 21 (FGF21) contributed to the microenvironment communication between adipocytes and macrophages induced by the loss of MSTN. Moreover, the MSTN/SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. In summary, our findings suggest that brown adipocyte-derived MSTN regulated BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.
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Affiliation(s)
- Hui Wang
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China
| | - Shanshan Guo
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China
| | - Huanqing Gao
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China
| | - Jiyang Ding
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China
| | - Hongyun Li
- Department of Sports Medicine and Arthroscopy Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Xingyu Kong
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China
| | - Shuang Zhang
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China
| | - Muyang He
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Yonghao Feng
- Department of Endocrinology, Jinshan Hospital, Fudan University, Shanghai, China
| | - Wei Wu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Kexin Xu
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China
| | - Yuxuan Chen
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China
| | - Hanyin Zhang
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Tiemin Liu
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Xingxing Kong
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
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18
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Boychenko S, Egorova VS, Brovin A, Egorov AD. White-to-Beige and Back: Adipocyte Conversion and Transcriptional Reprogramming. Pharmaceuticals (Basel) 2024; 17:790. [PMID: 38931457 PMCID: PMC11206576 DOI: 10.3390/ph17060790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/11/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution of hereditary and behavioral factors, such as nutritional inadequacy, along with the influences of environment and reduced physical activity. Two types of adipose tissue widely known are white and brown. While white adipose tissue functions predominantly as a key energy storage, brown adipose tissue has a greater mass of mitochondria and expresses the uncoupling protein 1 (UCP1) gene, which allows thermogenesis and rapid catabolism. Even though white and brown adipocytes are of different origin, activation of the brown adipocyte differentiation program in white adipose tissue cells forces them to transdifferentiate into "beige" adipocytes, characterized by thermogenesis and intensive lipolysis. Nowadays, researchers in the field of small molecule medicinal chemistry and gene therapy are making efforts to develop new drugs that effectively overcome insulin resistance and counteract obesity. Here, we discuss various aspects of white-to-beige conversion, adipose tissue catabolic re-activation, and non-shivering thermogenesis.
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Affiliation(s)
- Stanislav Boychenko
- Gene Therapy Department, Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sirius, Russia; (S.B.); (A.B.)
| | - Vera S. Egorova
- Biotechnology Department, Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sirius, Russia
| | - Andrew Brovin
- Gene Therapy Department, Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sirius, Russia; (S.B.); (A.B.)
| | - Alexander D. Egorov
- Gene Therapy Department, Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sirius, Russia; (S.B.); (A.B.)
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19
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Bramel EE, Camejo WAE, Creamer TJ, Restrepo L, Saqib M, Bagirzadeh R, Zeng A, Mitchell JT, Stein-O’Brien GL, Pedroza AJ, Fischbein MP, Dietz HC, MacFarlane EG. Intrinsic Gata4 expression sensitizes the aortic root to dilation in a Loeys-Dietz syndrome mouse model. RESEARCH SQUARE 2024:rs.3.rs-4420617. [PMID: 38883722 PMCID: PMC11177966 DOI: 10.21203/rs.3.rs-4420617/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
Loeys-Dietz syndrome (LDS) is an aneurysm disorder caused by mutations that decrease transforming growth factor-β (TGF-β) signaling. Although aneurysms develop throughout the arterial tree, the aortic root is a site of heightened risk. To identify molecular determinants of this vulnerability, we investigated the heterogeneity of vascular smooth muscle cells (VSMCs) in the aorta of Tgfbr1 M318R/+ LDS mice by single cell and spatial transcriptomics. Reduced expression of components of the extracellular matrix-receptor apparatus and upregulation of stress and inflammatory pathways were observed in all LDS VSMCs. However, regardless of genotype, a subset of Gata4-expressing VSMCs predominantly located in the aortic root intrinsically displayed a less differentiated, proinflammatory profile. A similar population was also identified among aortic VSMCs in a human scRNAseq dataset. Postnatal VSMC-specific Gata4 deletion reduced aortic root dilation in LDS mice, suggesting that this factor sensitizes the aortic root to the effects of impaired TGF-β signaling.
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Affiliation(s)
- Emily E. Bramel
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Predoctoral Training in Human Genetics and Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Wendy A. Espinoza Camejo
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Predoctoral Training in Human Genetics and Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tyler J. Creamer
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Leda Restrepo
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Muzna Saqib
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Rustam Bagirzadeh
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Anthony Zeng
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jacob T. Mitchell
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Predoctoral Training in Human Genetics and Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Genevieve L. Stein-O’Brien
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Albert J. Pedroza
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Michael P. Fischbein
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Harry C. Dietz
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Elena Gallo MacFarlane
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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20
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Bai Y, Li J, Wei Y, Chen Z, Liu Z, Guo D, Jia X, Niu Y, Shi B, Zhang X, Zhao Z, Hu J, Han X, Wang J, Liu X, Li S. Proteome Analysis Related to Unsaturated Fatty Acid Synthesis by Interfering with Bovine Adipocyte ACSL1 Gene. Antioxidants (Basel) 2024; 13:641. [PMID: 38929080 PMCID: PMC11200461 DOI: 10.3390/antiox13060641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 06/28/2024] Open
Abstract
Unsaturated fatty acids (UFAs) in beef play a vital role in promoting human health. Long-chain fatty acyl-CoA synthase 1 (ACSL1) is a crucial gene for UFA synthesis in bovine adipocytes. To investigate the protein expression profile during UFA synthesis, we performed a proteomic analysis of bovine adipocytes by RNA interference and non-interference with ACSL1 using label-free techniques. A total of 3558 proteins were identified in both the NC and si-treated groups, of which 1428 were differentially expressed proteins (DEPs; fold change ≥ 1.2 or ≤ 0.83 and p-value < 0.05). The enrichment analysis of the DEPs revealed signaling pathways related to UFA synthesis or metabolism, including cAMP, oxytocin, fatty acid degradation, glycerol metabolism, insulin, and the regulation of lipolysis in adipocytes (p-value < 0.05). Furthermore, based on the enrichment analysis of the DEPs, we screened 50 DEPs that potentially influence the synthesis of UFAs and constructed an interaction network. Moreover, by integrating our previously published transcriptome data, this study established a regulatory network involving differentially expressed long non-coding RNAs (DELs), highlighting 21 DEPs and 13 DELs as key genes involved in UFA synthesis. These findings present potential candidate genes for further investigation into the molecular mechanisms underlying UFA synthesis in bovines, thereby offering insights to enhance the quality of beef and contribute to consumer health in future studies.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Zhidong Zhao
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (Y.B.); (J.L.); (Y.W.); (Z.C.); (Z.L.); (D.G.); (X.J.); (Y.N.); (B.S.); (X.Z.); (X.H.); (J.W.); (X.L.); (S.L.)
| | - Jiang Hu
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (Y.B.); (J.L.); (Y.W.); (Z.C.); (Z.L.); (D.G.); (X.J.); (Y.N.); (B.S.); (X.Z.); (X.H.); (J.W.); (X.L.); (S.L.)
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21
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Abebe BK, Wang H, Li A, Zan L. A review of the role of transcription factors in regulating adipogenesis and lipogenesis in beef cattle. J Anim Breed Genet 2024; 141:235-256. [PMID: 38146089 DOI: 10.1111/jbg.12841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/25/2023] [Accepted: 11/30/2023] [Indexed: 12/27/2023]
Abstract
In the past few decades, genomic selection and other refined strategies have been used to increase the growth rate and lean meat production of beef cattle. Nevertheless, the fast growth rates of cattle breeds are often accompanied by a reduction in intramuscular fat (IMF) deposition, impairing meat quality. Transcription factors play vital roles in regulating adipogenesis and lipogenesis in beef cattle. Meanwhile, understanding the role of transcription factors in regulating adipogenesis and lipogenesis in beef cattle has gained significant attention to increase IMF deposition and meat quality. Therefore, the aim of this paper was to provide a comprehensive summary and valuable insight into the complex role of transcription factors in adipogenesis and lipogenesis in beef cattle. This review summarizes the contemporary studies in transcription factors in adipogenesis and lipogenesis, genome-wide analysis of transcription factors, epigenetic regulation of transcription factors, nutritional regulation of transcription factors, metabolic signalling pathways, functional genomics methods, transcriptomic profiling of adipose tissues, transcription factors and meat quality and comparative genomics with other livestock species. In conclusion, transcription factors play a crucial role in promoting adipocyte development and fatty acid biosynthesis in beef cattle. They control adipose tissue formation and metabolism, thereby improving meat quality and maintaining metabolic balance. Understanding the processes by which these transcription factors regulate adipose tissue deposition and lipid metabolism will simplify the development of marbling or IMF composition in beef cattle.
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Affiliation(s)
- Belete Kuraz Abebe
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
- Department of Animal Science, Werabe University, Werabe, Ethiopia
| | - Hongbao Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Anning Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Linsen Zan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
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22
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Chen JF, Wang J, Chai J, Jin W, Ren QL, Ma Q, Lu QX, Sun JJ, Mo DL, Zhang JQ, Xing BS. Transcriptome profiling of longissimus dorsi during different prenatal stages to identify genes involved in intramuscular fat deposition in lean and obese pig breeds. Mol Biol Rep 2024; 51:386. [PMID: 38441676 PMCID: PMC10914898 DOI: 10.1007/s11033-023-09088-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 11/29/2023] [Indexed: 03/07/2024]
Abstract
BACKGROUND There was significant difference in muscle development between fat-type and lean-type pig breeds. METHODS AND RESULTS In current study, transcriptome analysis and bioinformatics analysis were used to compare the difference in longissimus dorsi (LD) muscle at three time-points (38 days post coitus (dpc), 58 dpc, and 78 dpc ) between Huainan (HN) and Large white (LW) pig breeds. A total of 24500 transcripts were obtained in 18 samples, and 2319, 2799, and 3713 differently expressed genes (DEGs) were identified between these two breeds at 38 dpc, 58 dpc, and 78 dpc, respectively. And the number and foldchange of DEGs were increased, the alternative splice also increased. The cluster analysis of DEGs indicated the embryonic development progress of LD muscle between these two breeds was different. There were 539 shared DEGs between HN and LW at three stages, and the top-shared DEGs were associated with muscle development and lipid deposition, such as KLF4, NR4A1, HSP70, ZBTB16 and so on. CONCLUSIONS The results showed DEGs between Huainan (HN) and Large white (LW) pig breeds, and contributed to the understanding the muscle development difference between HN and LW, and provided basic materials for improvement of meat quality.
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Affiliation(s)
- Jun Feng Chen
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Jing Wang
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Jin Chai
- Agricultural Ministry Key Laboratory of Swine Breeding and Genetics & Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
| | - Wei Jin
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Qiao Ling Ren
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Qiang Ma
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Qing Xia Lu
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Jia Jie Sun
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - De Lin Mo
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jia Qing Zhang
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China
| | - Bao Song Xing
- Henan Key Laboratory of Farm Animal Breeding and Nutritional Regulation, Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Huayuan Road No.116, Zhengzhou, 450002, Henan, China.
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23
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Wu S, Qiu C, Ni J, Guo W, Song J, Yang X, Sun Y, Chen Y, Zhu Y, Chang X, Sun P, Wang C, Li K, Han X. M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1. Nat Commun 2024; 15:1646. [PMID: 38388532 PMCID: PMC10883921 DOI: 10.1038/s41467-024-45899-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 02/06/2024] [Indexed: 02/24/2024] Open
Abstract
Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation.
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Affiliation(s)
- Suyang Wu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Chen Qiu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, China
- Key Laboratory of the Model Animal Research, Animal Core Facility of Nanjing Medical University, Nanjing, 211166, China
| | - Jiahao Ni
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Wenli Guo
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Jiyuan Song
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Xingyin Yang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Yulin Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Yanjun Chen
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Peng Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Chunxia Wang
- Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
| | - Kai Li
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China.
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, China.
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China.
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24
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Li B, Liu S, He Z, Luo E, Liu H. The role of zinc finger proteins in the fate determination of mesenchymal stem cells during osteogenic and adipogenic differentiation. Int J Biochem Cell Biol 2024; 167:106507. [PMID: 38142772 DOI: 10.1016/j.biocel.2023.106507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 12/26/2023]
Abstract
Zinc finger proteins (ZFPs) constitute a crucial group of transcription factors widely present in various organisms. They act as transcription factors, nucleases, and RNA-binding proteins, playing significant roles in cell differentiation, growth, and development. With extensive research on ZFPs, their roles in the determination of mesenchymal stem cells (MSCs) fate during osteogenic and adipogenic differentiation processes have become increasingly clear. ZFP521, for instance, is identified as an inhibitor of the Wnt signaling pathway and RUNX2's transcriptional activity, effectively suppressing osteogenic differentiation. Moreover, ZFP217 contributes to the inhibition of adipogenic differentiation by reducing the M6A level of the cell cycle regulator cyclin D1 (CCND1). In addition, other ZFPs can also influence the fate of mesenchymal stem cells (MSCs) during osteogenic and adipogenic differentiation through various signaling pathways, transcription factors, and epigenetic controls, participating in the subsequent differentiation and maturation of precursor cells. Given the prevalent occurrence of osteoporosis, obesity, and related metabolic disorders, a comprehensive understanding of the regulatory mechanisms balancing bone and fat metabolism is essential, with a particular focus on the fate determination of MSCs in osteogenic and adipogenic differentiation. In this review, we provide a detailed summary of how zinc finger proteins influence the osteogenic and adipogenic differentiation of MSCs through different signaling pathways, transcription factors, and epigenetic mechanisms. Additionally, we outline the regulatory mechanisms of ZFPs in controlling osteogenic and adipogenic differentiation based on various stages of MSC differentiation.
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Affiliation(s)
- Bolun Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Shibo Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Ze He
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - En Luo
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Hanghang Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
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25
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Gong X, Liu Y, Liu H, Cao N, Zeng L, Tian M, Zeng C, Hu Y, Zhang R, Chen Y, Wu G. Re-analysis of single-cell transcriptomics reveals a critical role of macrophage-like smooth muscle cells in advanced atherosclerotic plaque. Theranostics 2024; 14:1450-1463. [PMID: 38389849 PMCID: PMC10879858 DOI: 10.7150/thno.87201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 01/05/2024] [Indexed: 02/24/2024] Open
Abstract
Aims: Smooth muscle cell (SMC) remodeling poses a critical feature in the development and progression of atherosclerosis. Although fate mapping and in silicon approaches have expanded SMC phenotypes in atherosclerosis, it still remains elusive about the contributions of individual SMC phenotypes and molecular dynamics to advanced atherosclerotic plaque. Methods: Using single-cell transcriptome, we investigated cellular compositions of human carotid plaque laden with atherosclerotic core, followed by in vivo experiments utilizing SMC-lineage tracing technology, bulk RNA sequencing (RNA-seq) and both in vivo and in vitro validation of the underlying molecular mechanism. Results: 5 functionally distinct SMC subtypes were uncovered based on transcriptional features (described as contractile, fibroblast-like, osteogenic, synthetic and macrophage-like) within the niche. A proinflammatory, macrophage-like SMC subtype displaying an intermediary phenotype between SMC and macrophage, exhibits prominent potential in destabilizing plaque. At the molecular level, we explored cluster-specific master regulons by algorithm, and identified interferon regulatory factor-8 (IRF8) as a potential stimulator of SMC-to-macrophage transdifferentiation via activating nuclear factor-κB (NF-κB) signaling. Conclusions: Our study illustrates a comprehensive cell atlas and molecular landscape of advanced atherosclerotic lesion, which might renovate current understanding of SMC biology in atherosclerosis.
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Affiliation(s)
- Xue Gong
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, P.R. China
- Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, P. R. China
- Department of Cardiology, No. 926 Hospital, Joint Logistics Support Force of PLA, P.R. China
| | - Yunchang Liu
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China
- Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, P. R. China
| | - Huiying Liu
- College of Pulmonary and Critical Care Medicine, The 8th Medical Centre, Chinese PLA General Hospital, Beijing, P.R. China
| | - Nian Cao
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, P.R. China
| | - Liping Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China
- Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, P. R. China
| | - Miao Tian
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China
- Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, P. R. China
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China
- Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, P. R. China
| | - Yijie Hu
- Department of Cardiac Surgery, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China
| | - Runjun Zhang
- Department of Cardiology, No. 926 Hospital, Joint Logistics Support Force of PLA, P.R. China
| | - Yundai Chen
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, P.R. China
| | - Gengze Wu
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China
- Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, P. R. China
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26
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Zhu W, Bu G, Hu R, Zhang J, Qiao L, Zhou K, Wang T, Li Q, Zhang J, Wu L, Xie Y, Hu T, Yang S, Guan J, Chu X, Shi J, Zhang X, Lu F, Liu X, Miao YL. KLF4 facilitates chromatin accessibility remodeling in porcine early embryos. SCIENCE CHINA. LIFE SCIENCES 2024; 67:96-112. [PMID: 37698691 DOI: 10.1007/s11427-022-2349-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/20/2023] [Indexed: 09/13/2023]
Abstract
Chromatin accessibility remodeling driven by pioneer factors is critical for the development of early embryos. Current studies have illustrated several pioneer factors as being important for agricultural animals, but what are the pioneer factors and how the pioneer factors remodel the chromatin accessibility in porcine early embryos is not clear. By employing low-input DNase-seq (liDNase-seq), we profiled the landscapes of chromatin accessibility in porcine early embryos and uncovered a unique chromatin accessibility reprogramming pattern during porcine preimplantation development. Our data revealed that KLF4 played critical roles in remodeling chromatin accessibility in porcine early embryos. Knocking down of KLF4 led to the reduction of chromatin accessibility in early embryos, whereas KLF4 overexpression promoted the chromatin openness in porcine blastocysts. Furthermore, KLF4 deficiency resulted in mitochondrial dysfunction and developmental failure of porcine embryos. In addition, we found that overexpression of KLF4 in blastocysts promoted lipid droplet accumulation, whereas knockdown of KLF4 disrupted this process. Taken together, our study revealed the chromatin accessibility dynamics and identified KLF4 as a key regulator in chromatin accessibility and cellular metabolism during porcine preimplantation embryo development.
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Affiliation(s)
- Wei Zhu
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Guowei Bu
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Ruifeng Hu
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Jixiang Zhang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing, 100101, China
| | - Lianyong Qiao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing, 100101, China
| | - Kai Zhou
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Tingting Wang
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Qiao Li
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Jingjing Zhang
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Linhui Wu
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Yali Xie
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing, 100101, China
| | - Taotao Hu
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Shichun Yang
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Jiaqi Guan
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Xiaoyu Chu
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Juanjuan Shi
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Xia Zhang
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China
| | - Falong Lu
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Xin Liu
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China.
| | - Yi-Liang Miao
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, China.
- Frontiers Science Center for Animal Breeding and Sustainable Production, Huazhong Agricultural University, Wuhan, 430070, China.
- Hubei Hongshan Laboratory, Wuhan, 430070, China.
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Wu J, Wang Z, Cai M, Wang X, Lo B, Li Q, He JC, Lee K, Fu J. GPR56 Promotes Diabetic Kidney Disease Through eNOS Regulation in Glomerular Endothelial Cells. Diabetes 2023; 72:1652-1663. [PMID: 37579299 PMCID: PMC10588296 DOI: 10.2337/db23-0124] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 08/09/2023] [Indexed: 08/16/2023]
Abstract
Although glomerular endothelial dysfunction is well recognized as contributing to the pathogenesis of diabetic kidney disease (DKD), the molecular pathways contributing to DKD pathogenesis in glomerular endothelial cells (GECs) are only partially understood. To uncover pathways that are differentially regulated in early DKD that may contribute to disease pathogenesis, we recently conducted a transcriptomic analysis of isolated GECs from diabetic NOS3-null mice. The analysis identified several potential mediators of early DKD pathogenesis, one of which encoded an adhesion G protein-coupled receptor-56 (GPR56), also known as ADGRG1. Enhanced glomerular expression of GPR56 was observed in human diabetic kidneys, which was negatively associated with kidney function. Using cultured mouse GECs, we observed that GPR56 expression was induced with exposure to advanced glycation end products, as well as in high-glucose conditions, and its overexpression resulted in decreased phosphorylation and expression of endothelial nitric oxide synthase (eNOS). This effect on eNOS by GPR56 was mediated by coupling of Gα12/13-RhoA pathway activation and Gαi-mediated cAMP/PKA pathway inhibition. The loss of GPR56 in mice led to a significant reduction in diabetes-induced albuminuria and glomerular injury, which was associated with reduced oxidative stress and restoration of eNOS expression in GECs. These findings suggest that GPR56 promotes DKD progression mediated, in part, through enhancing glomerular endothelial injury and dysfunction. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Jinshan Wu
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhihong Wang
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Minchao Cai
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Xuan Wang
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Benjamin Lo
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Qifu Li
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - John Cijiang He
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY
- Renal Program, James J. Peters Veterans Affairs Medical Center at Bronx, Bronx, NY
| | - Kyung Lee
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jia Fu
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY
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28
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Wang H, Akbari-Alavijeh S, Parhar RS, Gaugler R, Hashmi S. Partners in diabetes epidemic: A global perspective. World J Diabetes 2023; 14:1463-1477. [PMID: 37970124 PMCID: PMC10642420 DOI: 10.4239/wjd.v14.i10.1463] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/01/2023] [Accepted: 09/01/2023] [Indexed: 10/09/2023] Open
Abstract
There is a recent increase in the worldwide prevalence of both obesity and diabetes. In this review we assessed insulin signaling, genetics, environment, lipid metabolism dysfunction and mitochondria as the major determinants in diabetes and to identify the potential mechanism of gut microbiota in diabetes diseases. We searched relevant articles, which have key information from laboratory experiments, epidemiological evidence, clinical trials, experimental models, meta-analysis and review articles, in PubMed, MEDLINE, EMBASE, Google scholars and Cochrane Controlled Trial Database. We selected 144 full-length articles that met our inclusion and exclusion criteria for complete assessment. We have briefly discussed these associations, challenges, and the need for further research to manage and treat diabetes more efficiently. Diabetes involves the complex network of physiological dysfunction that can be attributed to insulin signaling, genetics, environment, obesity, mitochondria and stress. In recent years, there are intriguing findings regarding gut microbiome as the important regulator of diabetes. Valid approaches are necessary for speeding medical advances but we should find a solution sooner given the burden of the metabolic disorder - What we need is a collaborative venture that may involve laboratories both in academia and industries for the scientific progress and its application for the diabetes control.
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Affiliation(s)
- Huan Wang
- College of Bioscience and Biotechnology, Shenyang Agricultural University, Shenyang 110866, Liaoning Province, China
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
| | - Safoura Akbari-Alavijeh
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
- Department of Food Science and Technology, College of Agriculture, Isfahan University of Technology, Isfahan 84156-83111, Iran
| | - Ranjit S Parhar
- Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Randy Gaugler
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
| | - Sarwar Hashmi
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
- Research and Diagnostics, Ghazala and Sanya Hashmi Foundation, Holmdel, NJ 07733, United States
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Li K, Li B, Zhang D, Du T, Zhou H, Dai G, Yan Y, Gao N, Zhuang X, Liao X, Liu C, Dong Y, Chen D, Qu LH, Ou J, Yang JH, Huang ZP. The translational landscape of human vascular smooth muscle cells identifies novel short open reading frame-encoded peptide regulators for phenotype alteration. Cardiovasc Res 2023; 119:1763-1779. [PMID: 36943764 DOI: 10.1093/cvr/cvad044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 01/09/2023] [Accepted: 01/19/2023] [Indexed: 03/23/2023] Open
Abstract
AIMS The plasticity of vascular smooth muscle cells (VSMCs) enables them to alter phenotypes under various physiological and pathological stimuli. The alteration of VSMC phenotype is a key step in vascular diseases, including atherosclerosis. Although the transcriptome shift during VSMC phenotype alteration has been intensively investigated, uncovering multiple key regulatory signalling pathways, the translatome dynamics in this cellular process, remain largely unknown. Here, we explored the genome-wide regulation at the translational level of human VSMCs during phenotype alteration. METHODS AND RESULTS We generated nucleotide-resolution translatome and transcriptome data from human VSMCs undergoing phenotype alteration. Deep sequencing of ribosome-protected fragments (Ribo-seq) revealed alterations in protein synthesis independent of changes in messenger ribonucleicacid levels. Increased translational efficiency of many translational machinery components, including ribosomal proteins, eukaryotic translation elongation factors and initiation factors were observed during the phenotype alteration of VSMCs. In addition, hundreds of candidates for short open reading frame-encoded polypeptides (SEPs), a class of peptides containing 200 amino acids or less, were identified in a combined analysis of translatome and transcriptome data with a high positive rate in validating their coding capability. Three evolutionarily conserved SEPs were further detected endogenously by customized antibodies and suggested to participate in the pathogenesis of atherosclerosis by analysing the transcriptome and single cell RNA-seq data from patient atherosclerotic artery samples. Gain- and loss-of-function studies in human VSMCs and genetically engineered mice showed that these SEPs modulate the alteration of VSMC phenotype through different signalling pathways, including the mitogen-activated protein kinase pathway and p53 pathway. CONCLUSION Our study indicates that an increase in the capacity of translation, which is attributable to an increased quantity of translational machinery components, mainly controls alterations of VSMC phenotype at the level of translational regulation. In addition, SEPs could function as important regulators in the phenotype alteration of human VSMCs.
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Affiliation(s)
- Kang Li
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Bin Li
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, 135 Xingang Xi Road, Guangzhou 510275, China
| | - Dihua Zhang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Tailai Du
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Huimin Zhou
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Gang Dai
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Youchen Yan
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Nailin Gao
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Xiaodong Zhuang
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Xinxue Liao
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Chen Liu
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Yugang Dong
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Demeng Chen
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Liang-Hu Qu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, 135 Xingang Xi Road, Guangzhou 510275, China
| | - Jingsong Ou
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
| | - Jian-Hua Yang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, 135 Xingang Xi Road, Guangzhou 510275, China
| | - Zhan-Peng Huang
- 1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases (Sun Yat-sen University), 58 Zhongshan Er Road, Guangzhou 510080, China
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Yu R, Han H, Chu S, Ding Y, Jin S, Wang Y, Jiang W, Liu Y, Zou Y, Wang M, Liu Q, Sun G, Jiang B, Gong Y. CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ. Bone Res 2023; 11:29. [PMID: 37268647 DOI: 10.1038/s41413-023-00263-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 03/23/2023] [Accepted: 04/04/2023] [Indexed: 06/04/2023] Open
Abstract
Dysregulated lineage commitment of mesenchymal stem cells (MSCs) contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis. The intrinsic cellular mechanism that regulates MSC commitment remains unclear. Here, we identified Cullin 4B (CUL4B) as a critical regulator of MSC commitment. CUL4B is expressed in bone marrow MSCs (BMSCs) and downregulated with aging in mice and humans. Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation. Moreover, depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy. In addition, CUL4B deficiency in MSCs reduced bone strength. Mechanistically, CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδ expression, respectively. The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription. Collectively, this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs, which has therapeutic implications in osteoporosis.
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Affiliation(s)
- Ruiqi Yu
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Hong Han
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Shuxian Chu
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Yijun Ding
- The Key Laboratory of Liquid‒Solid Structural Evolution and Processing of Materials of Ministry of Education and Institute of Liquid Metal and Casting Technology, School of Materials Science and Engineering, Shandong University, Jinan, 250012, China
| | - Shiqi Jin
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Yufeng Wang
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Wei Jiang
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Yuting Liu
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Yongxin Zou
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Molin Wang
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Qiao Liu
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Gongping Sun
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Baichun Jiang
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
| | - Yaoqin Gong
- The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
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Roberti A, Tejedor JR, Díaz-Moreno I, López V, Santamarina-Ojeda P, Pérez RF, Urdinguio RG, Concellón C, Martínez-Chantar ML, Fernández-Morera JL, Díaz-Quintana A, Del Amo V, Fernández AF, Fraga MF. Nicotinamide N-methyltransferase (NNMT) regulates the glucocorticoid signaling pathway during the early phase of adipogenesis. Sci Rep 2023; 13:8293. [PMID: 37217546 DOI: 10.1038/s41598-023-34916-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 05/09/2023] [Indexed: 05/24/2023] Open
Abstract
Obesity is associated with adipose tissue dysfunction through the differentiation and expansion of pre-adipocytes to adipocytes (hyperplasia) and/or increases in size of pre-existing adipocytes (hypertrophy). A cascade of transcriptional events coordinates the differentiation of pre-adipocytes into fully differentiated adipocytes; the process of adipogenesis. Although nicotinamide N-methyltransferase (NNMT) has been associated with obesity, how NNMT is regulated during adipogenesis, and the underlying regulatory mechanisms, remain undefined. In present study we used genetic and pharmacological approaches to elucidate the molecular signals driving NNMT activation and its role during adipogenesis. Firstly, we demonstrated that during the early phase of adipocyte differentiation NNMT is transactivated by CCAAT/Enhancer Binding Protein beta (CEBPB) in response to glucocorticoid (GC) induction. We found that Nnmt knockout, using CRISPR/Cas9 approach, impaired terminal adipogenesis by influencing the timing of cellular commitment and cell cycle exit during mitotic clonal expansion, as demonstrated by cell cycle analysis and RNA sequencing experiments. Biochemical and computational methods showed that a novel small molecule, called CC-410, stably binds to and highly specifically inhibits NNMT. CC-410 was, therefore, used to modulate protein activity during pre-adipocyte differentiation stages, demonstrating that, in line with the genetic approach, chemical inhibition of NNMT at the early stages of adipogenesis impairs terminal differentiation by deregulating the GC network. These congruent results conclusively demonstrate that NNMT is a key component of the GC-CEBP axis during the early stages of adipogenesis and could be a potential therapeutic target for both early-onset obesity and glucocorticoid-induced obesity.
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Affiliation(s)
- Annalisa Roberti
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Spain
- Foundation for Biomedical Research and Innovation in Asturias (FINBA), 33011, Oviedo, Spain
- Health Research Institute of Asturias (ISPA), Av. del Hospital Universitario, 33011, Oviedo, Asturias, Spain
- University Institute of Oncology (IUOPA), University of Oviedo, 33006, Oviedo, Spain
| | - Juan Ramon Tejedor
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Spain
- Foundation for Biomedical Research and Innovation in Asturias (FINBA), 33011, Oviedo, Spain
- Health Research Institute of Asturias (ISPA), Av. del Hospital Universitario, 33011, Oviedo, Asturias, Spain
- University Institute of Oncology (IUOPA), University of Oviedo, 33006, Oviedo, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 28029, Madrid, Spain
| | - Irene Díaz-Moreno
- Institute for Chemical Research (IIQ), Scientific Research Centre Isla de la Cartuja (cicCartuja), University of Seville - Spanish National Research Council (CSIC), Seville, Spain
| | - Virginia López
- Foundation for Biomedical Research and Innovation in Asturias (FINBA), 33011, Oviedo, Spain
- Health Research Institute of Asturias (ISPA), Av. del Hospital Universitario, 33011, Oviedo, Asturias, Spain
- University Institute of Oncology (IUOPA), University of Oviedo, 33006, Oviedo, Spain
| | - Pablo Santamarina-Ojeda
- Foundation for Biomedical Research and Innovation in Asturias (FINBA), 33011, Oviedo, Spain
- Health Research Institute of Asturias (ISPA), Av. del Hospital Universitario, 33011, Oviedo, Asturias, Spain
- University Institute of Oncology (IUOPA), University of Oviedo, 33006, Oviedo, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 28029, Madrid, Spain
| | - Raúl F Pérez
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Spain
- Foundation for Biomedical Research and Innovation in Asturias (FINBA), 33011, Oviedo, Spain
- Health Research Institute of Asturias (ISPA), Av. del Hospital Universitario, 33011, Oviedo, Asturias, Spain
- University Institute of Oncology (IUOPA), University of Oviedo, 33006, Oviedo, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 28029, Madrid, Spain
| | - Rocío G Urdinguio
- Foundation for Biomedical Research and Innovation in Asturias (FINBA), 33011, Oviedo, Spain
- Health Research Institute of Asturias (ISPA), Av. del Hospital Universitario, 33011, Oviedo, Asturias, Spain
- University Institute of Oncology (IUOPA), University of Oviedo, 33006, Oviedo, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 28029, Madrid, Spain
| | - Carmen Concellón
- Department of Organic and Inorganic Chemistry, University of Oviedo, Oviedo, Spain
| | - María Luz Martínez-Chantar
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance, Derio, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain
| | - Juan Luis Fernández-Morera
- Foundation for Biomedical Research and Innovation in Asturias (FINBA), 33011, Oviedo, Spain
- Health Research Institute of Asturias (ISPA), Av. del Hospital Universitario, 33011, Oviedo, Asturias, Spain
- Endocrinology and Nutrition Department, Hospital Vital Alvarez Buylla (HVAB), 33611, Mieres, Spain
| | - Antonio Díaz-Quintana
- Institute for Chemical Research (IIQ), Scientific Research Centre Isla de la Cartuja (cicCartuja), University of Seville - Spanish National Research Council (CSIC), Seville, Spain
| | - Vicente Del Amo
- Department of Organic and Inorganic Chemistry, University of Oviedo, Oviedo, Spain
| | - Agustín F Fernández
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Spain.
- Foundation for Biomedical Research and Innovation in Asturias (FINBA), 33011, Oviedo, Spain.
- Health Research Institute of Asturias (ISPA), Av. del Hospital Universitario, 33011, Oviedo, Asturias, Spain.
- University Institute of Oncology (IUOPA), University of Oviedo, 33006, Oviedo, Spain.
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 28029, Madrid, Spain.
| | - Mario F Fraga
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Spain.
- Foundation for Biomedical Research and Innovation in Asturias (FINBA), 33011, Oviedo, Spain.
- Health Research Institute of Asturias (ISPA), Av. del Hospital Universitario, 33011, Oviedo, Asturias, Spain.
- University Institute of Oncology (IUOPA), University of Oviedo, 33006, Oviedo, Spain.
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 28029, Madrid, Spain.
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Li X, Zeng X, Kim D, Jiang J, Wei F, Zhang J, Chai B, Fu L, Lee Y, Kim C, Chen H. Krüppel-like factor 4 (KLF4) facilitates lipid production in immortalized human sebocytes via regulating the expression of SREBP1. Biochem Biophys Res Commun 2023; 667:146-152. [PMID: 37229823 DOI: 10.1016/j.bbrc.2023.05.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/10/2023] [Accepted: 05/13/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Acne is associated with the excessive production of sebum, a complex mixture of lipids, in the sebaceous glands. The transcription factor Krüppel-like factor 4 (KLF4) plays an important role in skin morphogenesis, but its role in sebum production by sebocytes is not well known. PURPOSE In this study, we investigated the possible action mechanism of KLF4 during calcium-induced lipogenesis in immortalized human sebocytes. METHODS Sebocytes were treated with calcium, and lipid production was confirmed by thin-layer chromatography (TLC) and Oil Red O staining. To investigate the effect of KLF4, sebocytes were transduced with the KLF4-overexpressing adenovirus, and then lipid production was evaluated. RESULTS Calcium treatment resulted in increased sebum production in terms of squalene synthesis in sebocytes. In addition, calcium increased the expression of lipogenic regulators such as sterol-regulatory element binding protein 1 (SREBP1), sterol-regulatory element binding protein 2 (SREBP2), and stearoyl-CoA desaturase (SCD). Similarly, the expression of KLF4 was increased by calcium in sebocytes. To investigate the effect of KLF4, we overexpressed KLF4 in sebocytes using recombinant adenovirus. As a result, KLF4 overexpression increased the expression of SREBP1, SREBP2, and SCD. Parallel to this result, lipid production was also increased by KLF4 overexpression. Chromatin immunoprecipitation revealed the binding of KLF4 to the SREBP1 promoter, indicating that KLF4 may directly regulate the expression of lipogenic regulators. CONCLUSION These results suggest that KLF4 is a novel regulator of lipid production in sebocytes.
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Affiliation(s)
- XueMei Li
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China; Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China
| | - Xin Zeng
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China; Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China
| | - DoYeon Kim
- Department of Dermatology, Chungnam National University School of Medicine, Chungnam National University Hospital, Daejeon, 35015, South Korea
| | - Jian Jiang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Fen Wei
- Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China
| | - JingYu Zhang
- Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China; Shenzhen University Medical School, Shenzhen, 518060, China
| | - Bao Chai
- Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China; Department of Dermatology, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518052, China
| | - Li Fu
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and Shenzhen University International Cancer Center, Shenzhen University Medical School, Shenzhen, 518060, China
| | - Young Lee
- Department of Dermatology, Chungnam National University School of Medicine, Chungnam National University Hospital, Daejeon, 35015, South Korea
| | - ChangDeok Kim
- Department of Dermatology, Chungnam National University School of Medicine, Chungnam National University Hospital, Daejeon, 35015, South Korea.
| | - HongXiang Chen
- Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China; Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Mohan UP, Pichiah PBT, Arunachalam S. Adriamycin downregulates the expression of KLF4 in cardiomyocytes in vitro and contributes to impaired cardiac energy metabolism in Adriamycin-induced cardiomyopathy. 3 Biotech 2023; 13:162. [PMID: 37152000 PMCID: PMC10160296 DOI: 10.1007/s13205-023-03584-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 04/23/2023] [Indexed: 05/09/2023] Open
Abstract
Adriamycin is a well-known anthracycline chemotherapeutic agent widely used in treating a variety of malignancies. However, Adriamycin's clinical use is limited due to its adverse side-effects, most importantly cardiomyopathy. Adriamycin-induced cardiotoxicity reportedly includes mitochondrial dysfunction. We hypothesize that modulation of KLF4, a key regulator of cardiac mitochondrial homeostasis might play a role in the development of Adriamycin-induced cardiomyopathy. Therefore, in the current work, we evaluated the interaction of Adriamycin with KLF4 and its subsequent downstream targets. Molecular docking revealed that Adriamycin interacts strongly with KLF4 at residues Thr 448, Arg 452, Ser 444 falls within C2H2 motif which is the active site. Quantitative real-time PCR also revealed that KLF4 is downregulated by Adriamycin in cardiomyocytes in vitro. The expression of KLF4 is downregulated in a dose-dependent manner, with a 0.12 ± 0.09-fold (p ≤ 0.05, n = 3) downregulation at a low dosage and 0.21 ± 0.02-fold (p ≤ 0.05, n = 3) downregulation at high dosage. Deficiency of KLF4 leads to an impairment of PPARγ that consequently supresses the proteins/enzymes involved in the fatty acid metabolism. Adriamycin-mediated suppression of KLF4 also affected the expression of PPARα in vitro. PPARα dysfunction is likely to cause defects in β-oxidation which ultimately results in impaired ATP synthesis. Cardiac cells are thus forced to switch over the substrate from free fatty acid to glucose. Moreover, Adriamycin elevates the expression of PPARβ due to downregulation of KLF4 leads to increased myocardial glucose utilization. Thus, a change in substrate preference affects the flexibility of metabolic network culminating in diminished energy production and other regulatory activities, altogether contributing to the development of cardiomyopathy. Thus, we conclude that the effect of Adriamycin on KLF4 disrupts mitochondrial homeostasis and lipid/glucose homeostasis resulting in a reduction of ATP synthesis which ultimately results in dilated cardiomyopathy.
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Affiliation(s)
- Uma Priya Mohan
- Centre for Cardiovascular and Adverse Drug Reactions, Department of Biotechnology, School of Bio, Chemical and Processing Engineering, Kalasalingam Academy of Research and Education, Krishnankoil, Virudhunagar Dt., Tamilnadu, 626126 India
| | - P. B. Tirupathi Pichiah
- Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu 620024 India
| | - Sankarganesh Arunachalam
- Centre for Cardiovascular and Adverse Drug Reactions, Department of Biotechnology, School of Bio, Chemical and Processing Engineering, Kalasalingam Academy of Research and Education, Krishnankoil, Virudhunagar Dt., Tamilnadu, 626126 India
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Chu DT, Thi YVN, Chew NW. Histone modifications in fat metabolism and obesity. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 197:135-152. [PMID: 37019590 DOI: 10.1016/bs.pmbts.2023.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
The World Health Organization (WHO) has identified the obesity epidemic as one of the leading causes of overall morbidity and mortality. Obesity affects individual health, and quality of life and has negative long-term economic implications on society and the entire country. In recent years, studies on histone modifications in fat metabolism and obesity have received great attention. Processes such as methylation, histone modification, chromatin remodeling, and microRNA expression are mechanisms in epigenetic regulation. These processes play a particularly important role in cell development and differentiation through gene regulation. In this chapter, we discuss the types of histone modifications in adipose tissue under different conditions, the role of histone modifications in adipose tissue development, and the relationship between histone modifications and biosynthesis in the body. In addition, the chapter provides detailed information on histone modifications in obesity, the relationship between histone modifications and food consumption status, and the role of histone modifications in overweight and obesity.
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Hatzmann FM, Großmann S, Waldegger P, Wiegers GJ, Mandl M, Rauchenwald T, Pierer G, Zwerschke W. Dipeptidyl peptidase-4 cell surface expression marks an abundant adipose stem/progenitor cell population with high stemness in human white adipose tissue. Adipocyte 2022; 11:601-615. [PMID: 36168895 PMCID: PMC9542856 DOI: 10.1080/21623945.2022.2129060] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The capacity of adipose stem/progenitor cells (ASCs) to undergo self-renewal and differentiation is crucial for adipose tissue homoeostasis, regeneration and expansion. However, the heterogeneous ASC populations of the adipose lineage constituting adipose tissue are not precisely known. In the present study, we demonstrate that cell surface expression of dipeptidyl peptidase-4 (DPP4)/cluster of differentiation 26 (CD26) subdivides the DLK1-/CD34+/CD45-/CD31- ASC pool of human white adipose tissues (WATs) into two large populations. Ex vivo, DPP4+ ASCs possess higher self-renewal and proliferation capacity and lesser adipocyte differentiation potential than DDP4- ASCs. The knock-down of DPP4 in ASC leads to significantly reduced proliferation and self-renewal capacity, while adipogenic differentiation is increased. Ectopic overexpression of DPP4 strongly inhibits adipogenesis. Moreover, in whole mount stainings of human subcutaneous (s)WAT, we detect DPP4 in CD34+ ASC located in the vascular stroma surrounding small blood vessels and in mature adipocytes. We conclude that DPP4 is a functional marker for an abundant ASC population in human WAT with high proliferation and self-renewal potential and low adipogenic differentiation capacity.
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Affiliation(s)
- Florian M Hatzmann
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria,Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | - Sonja Großmann
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria,Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | - Petra Waldegger
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria,Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | - G Jan Wiegers
- Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria
| | - Markus Mandl
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria,Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | - Tina Rauchenwald
- Department of Plastic and Reconstructive Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Gerhard Pierer
- Department of Plastic and Reconstructive Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Werner Zwerschke
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria,Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria,CONTACT Werner Zwerschke Head of the Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck
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Khan F, Khan H, Khan A, Yamasaki M, Moustaid-Moussa N, Al-Harrasi A, Rahman SM. Autophagy in adipogenesis: Molecular mechanisms and regulation by bioactive compounds. Biomed Pharmacother 2022; 155:113715. [PMID: 36152415 DOI: 10.1016/j.biopha.2022.113715] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/19/2022] [Accepted: 09/19/2022] [Indexed: 11/02/2022] Open
Abstract
White adipose tissue expands rapidly due to increased adipocyte number (hyperplasia) and size (hypertrophy), which results in obesity. Adipogenesis is a process of the formation of mature adipocytes from precursor cells. Additionally, obesity-related metabolic complications, such as fatty liver and insulin resistance, are linked to adipogenesis. On the contrary, autophagy is a catabolic process; essential to maintain cellular homeostasis via the degradation or recycling of unnecessary or damaged components. Importantly, autophagy dictates obesity and adipogenesis. Hence, a clear understanding of how autophagy regulates adipogenesis is crucial for drug development and the prevention and treatment of obesity and its associated disorders, such as type 2 diabetes, cardiovascular disease, and cancer. In this review, we highlighted recent findings regarding the crosstalk between adipogenesis and autophagy, as well as the molecules involved. Furthermore, the review discussed how bioactive compounds regulate adipogenesis by manipulating autophagy and underlying molecular mechanisms. Based on in vitro and animal studies, we summarized the effects of bioactive compounds on adipogenesis and autophagy. Hence, human studies are necessary to validate the effectiveness and optimal dosage of these bioactive compounds.
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Affiliation(s)
- Faizullah Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman; Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan 23200 Khyber Pakhtunkhwa, Pakistan
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan 23200 Khyber Pakhtunkhwa, Pakistan
| | - Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman
| | - Masao Yamasaki
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan
| | - Naima Moustaid-Moussa
- Texas Tech University, Nutritional Sciences, Lubbock, TX 79409, USA; Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman
| | - Shaikh Mizanoor Rahman
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman.
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37
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Raza SHA, Pant SD, Wani AK, Mohamed HH, Khalifa NE, Almohaimeed HM, Alshanwani AR, Assiri R, Aggad WS, Noreldin AE, Abdelnour SA, Wang Z, Zan L. Krüppel-like factors family regulation of adipogenic markers genes in bovine cattle adipogenesis. Mol Cell Probes 2022; 65:101850. [PMID: 35988893 DOI: 10.1016/j.mcp.2022.101850] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 08/13/2022] [Accepted: 08/13/2022] [Indexed: 02/07/2023]
Abstract
Intramuscular fat (IMF) content is a crucial determinant of meat quality traits in livestock. A network of transcription factors act in concert to regulate adipocyte formation and differentiation, which in turn influences intramuscular fat. Several genes and associated transcription factors have been reported to influence lipogenesis and adipogenesis during fetal and subsequent growth stage. Specifically in cattle, Krüppel-like factors (KLFs), which represents a family of transcription factors, have been reported to be involved in adipogenic differentiation and development. KLFs are a relatively large group of zinc-finger transcription factors that have a variety of functions in addition to adipogenesis. In mammals, the participation of KLFs in cell development and differentiation is well known. Specifically in the context of adipogenesis, KLFs function either as positive (KLF4, KLF5, KLF6, KLF8, KLF9, KLF10, KLF11, KLF12, KLF13, KLF14 and KLF15) or negative organizers (KLF2, KLF3 and KLF7), by a variety of different mechanisms such as crosstalk with C/EBP and PPARγ. In this review, we aim to summarize the potential functions of KLFs in regulating adipogenesis and associated pathways in cattle. Furthermore, the function of known bovine adipogenic marker genes, and associated transcription factors that regulate the expression of these marker genes is also summarized. Overall, this review will provide an overview of marker genes known to influence bovine adipogenesis and regulation of expression of these genes, to provide insights into leveraging these genes and transcription factors to enhance breeding programs, especially in the context of IMF deposition and meat quality.
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Affiliation(s)
- Sayed Haidar Abbas Raza
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, PR China.
| | - Sameer D Pant
- School of Agricultural, Environmental and Veterinary Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia
| | - Atif Khurshid Wani
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Punjab, (144411), India
| | - Hadeer H Mohamed
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, Egypt
| | - Norhan E Khalifa
- Department of Physiology, Faculty of Veterinary Medicine, Fuka, Matrouh University, Matrouh, 51744, Egypt
| | - Hailah M Almohaimeed
- Department of Basic Science, College of Medicine, Princess Nourah bint Abdulrahman University, P.O.Box 84428, Riyadh, 11671, Saudi Arabia
| | - Aliah R Alshanwani
- Physiology Department, College of Medicine, King Saud University, Saudi Arabia
| | - Rasha Assiri
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, 11671, Saudi Arabia
| | - Waheeb S Aggad
- Department of Anatomy, College of Medicine, University of Jeddah, P.O. Box 8304, Jeddah, 23234, Saudi Arabia
| | - Ahmed E Noreldin
- Histology and Cytology Department, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, Egypt
| | - Sameh A Abdelnour
- Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig, 44511, Egypt
| | - Zhe Wang
- Shanghai Collaborative Innovation Center of Agri-Seeds/School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, PR China.
| | - Linsen Zan
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, PR China.
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38
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Sun W, Zhang T, Hu S, Tang Q, Long X, Yang X, Gun S, Chen L. Chromatin accessibility landscape of stromal subpopulations reveals distinct metabolic and inflammatory features of porcine subcutaneous and visceral adipose tissue. PeerJ 2022; 10:e13250. [PMID: 35646489 PMCID: PMC9138157 DOI: 10.7717/peerj.13250] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 03/21/2022] [Indexed: 01/13/2023] Open
Abstract
Background Fat accumulation in visceral adipose tissue (VAT) confers increased risk for metabolic disorders of obesity, whereas accumulation of subcutaneous adipose tissue (SAT) is associated with lower risk and may be protective. Previous studies have shed light on the gene expression profile differences between SAT and VAT; however, the chromatin accessibility landscape differences and how the cis-regulatory elements govern gene expression changes between SAT and VAT are unknown. Methods Pig were used to characterize the differences in chromatin accessibility between the two adipose depots-derived stromal vascular fractions (SVFs) using DNase-sequencing (DNase-seq). Using integrated data from DNase-seq, H3K27ac ChIP-sequencing (ChIP-seq), and RNA-sequencing (RNA-seq), we investigated how the regulatory locus complexity regulated gene expression changes between SAT and VAT and the possible impact that these changes may have on the different biological functions of these two adipose depots. Results SVFs form SAT and VAT (S-SVF and V-SVF) have differential chromatin accessibility landscapes. The differential DNase I hypersensitive site (DHS)-associated genes, which indicate dynamic chromatin accessibility, were mainly involved in metabolic processes and inflammatory responses. Additionally, the Krüppel-like factor family of transcription factors were enriched in the differential DHSs. Furthermore, the chromatin accessibility data were highly associated with differential gene expression as indicated using H3K27ac ChIP-seq and RNA-seq data, supporting the validity of the differential gene expression determined using DNase-seq. Moreover, by combining epigenetic and transcriptomic data, we identified two candidate genes, NR1D1 and CRYM, could be crucial to regulate distinct metabolic and inflammatory characteristics between SAT and VAT. Together, these results uncovered differences in the transcription regulatory network and enriched the mechanistic understanding of the different biological functions between SAT and VAT.
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Affiliation(s)
- Wenyang Sun
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China,Key Laboratory of Pig Industry Sciences (Ministry of Agriculture), Chongqing Academy of Animal Science, Chongqing, China
| | - Tinghuan Zhang
- Key Laboratory of Pig Industry Sciences (Ministry of Agriculture), Chongqing Academy of Animal Science, Chongqing, China
| | - Silu Hu
- Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Qianzi Tang
- Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Xi Long
- Key Laboratory of Pig Industry Sciences (Ministry of Agriculture), Chongqing Academy of Animal Science, Chongqing, China
| | - Xu Yang
- College of Nursing, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Shuangbao Gun
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
| | - Lei Chen
- Key Laboratory of Pig Industry Sciences (Ministry of Agriculture), Chongqing Academy of Animal Science, Chongqing, China
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39
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Bécsi B, Kónya Z, Boratkó A, Kovács K, Erdődi F. Epigallocatechine-3-gallate Inhibits the Adipogenesis of Human Mesenchymal Stem Cells via the Regulation of Protein Phosphatase-2A and Myosin Phosphatase. Cells 2022; 11:cells11101704. [PMID: 35626740 PMCID: PMC9140100 DOI: 10.3390/cells11101704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 02/01/2023] Open
Abstract
Epigallocatechin-3-gallate (EGCG) has widespread effects on adipocyte development. However, the molecular mechanisms of EGCG are not fully understood. We investigate the adipogenic differentiation of human-derived mesenchymal stem cells, including lipid deposition and changes in the expression and phosphorylation of key transcription factors, myosin, protein phosphatase-2A (PP2A), and myosin phosphatase (MP). On day 6 of adipogenic differentiation, EGCG (1–20 µM) suppressed lipid droplet formation, which was counteracted by an EGCG-binding peptide for the 67 kDa laminin receptor (67LR), suggesting that EGCG acts via 67LR. EGCG decreased the phosphorylation of CCAAT-enhancer-binding protein beta via the activation of PP2A in a protein kinase A (PKA)-dependent manner, leading to the partial suppression of peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin expression. Differentiated cells exhibited a rounded shape, cortical actin filaments, and lipid accumulation. The EGCG treatment induced cell elongation, stress fiber formation, and less lipid accumulation. These effects were accompanied by the degradation of the MP target subunit-1 and increased the phosphorylation of the 20 kDa myosin light chain. Our results suggest that EGCG acts as an agonist of 67LR to inhibit adipogenesis via the activation of PP2A and suppression of MP. These events are coupled with the decreased phosphorylation and expression levels of adipogenic transcription factors and changes in cell shape, culminating in curtailed adipogenesis.
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Affiliation(s)
- Bálint Bécsi
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (Z.K.); (A.B.); (K.K.)
| | - Zoltán Kónya
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (Z.K.); (A.B.); (K.K.)
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Anita Boratkó
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (Z.K.); (A.B.); (K.K.)
| | - Katalin Kovács
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (Z.K.); (A.B.); (K.K.)
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Ferenc Erdődi
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (Z.K.); (A.B.); (K.K.)
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
- Correspondence: ; Tel.: +36-52-412345
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40
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Sarver DC, Xu C, Carreno D, Arking A, Terrillion CE, Aja S, Wong GW. CTRP11 contributes modestly to systemic metabolism and energy balance. FASEB J 2022; 36:e22347. [PMID: 35579659 PMCID: PMC9164276 DOI: 10.1096/fj.202200189rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/23/2022] [Accepted: 04/29/2022] [Indexed: 12/18/2022]
Abstract
C1q/TNF‐related proteins (CTRP1‐15) constitute a conserved group of secreted proteins of the C1q family with diverse functions. In vitro studies have shown that CTRP11/C1QL4 can inhibit adipogenesis, antagonize myoblast fusion, and promote testosterone synthesis and secretion. Whether CTRP11 is required for these processes in vivo remains unknown. Here, we show that knockout (KO) mice lacking CTRP11 have normal skeletal muscle mass and function, and testosterone level, suggesting that CTRP11 is dispensable for skeletal muscle development and testosterone production. We focused our analysis on whether this nutrient‐responsive secreted protein plays a role in controlling sugar and fat metabolism. At baseline when mice are fed a standard chow, CTRP11 deficiency affects metabolic parameters in a sexually dimorphic manner. Only Ctrp11‐KO female mice have significantly higher fasting serum ketones and reduced physical activity. In the refeeding phase following food withdrawal, Ctrp11‐KO female mice have reduced food intake and increased metabolic rate and energy expenditure, highlighting CTRP11’s role in fasting–refeeding response. When challenged with a high‐fat diet to induce obesity and metabolic dysfunction, CTRP11 deficiency modestly exacerbates obesity‐induced glucose intolerance, with more pronounced effects seen in Ctrp11‐KO male mice. Switching to a low‐fat diet after obesity induction results in greater fat loss in wild type relative to KO male mice, suggesting impaired response to obesity reversal and reduced metabolic flexibility in the absence of CTRP11. Collectively, our data provide genetic evidence for novel sex‐dependent metabolic regulation by CTRP11, but note the overall modest contribution of CTRP11 to systemic energy homeostasis.
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Affiliation(s)
- Dylan C Sarver
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Cheng Xu
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Dana Carreno
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alexander Arking
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Chantelle E Terrillion
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Susan Aja
- Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - G William Wong
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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41
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Jiang M, Huang Y, Hu L, Wu H, Liu Y, Ni K, Zhang X, Sun Y, Gu X. The transcription factor CCAAT/enhancer-binding protein β in spinal microglia contributes to pre-operative stress-induced prolongation of postsurgical pain. Mol Pain 2022; 18:17448069221099360. [PMID: 35451875 PMCID: PMC9257637 DOI: 10.1177/17448069221099360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Prolongation of postsurgical pain caused by pre-operative stress is a clinically significant problem, although the mechanisms are not fully understood. Stress can promote the pro-inflammatory activation of microglia, and the transcription factor CCAAT/enhancer-binding protein (C/EBP) β regulates pro-inflammatory gene expression in microglia. Therefore, we speculated that C/EBPβ in spinal microglia may have critical roles in the development of chronic postsurgical pain. Accordingly, in this study, we used a single prolonged stress (SPS) procedure and plantar incisions to evaluate the roles of C/EBPβ in postsurgical pain. Our experiments showed that SPS exposure prolonged mechanical allodynia, increased the expression of C/EBPβ and pro-inflammatory cytokines, and potentiated the activation of spinal microglia. Subsequently, microinjection of C/EBPβ siRNA attenuated the duration of SPS-prolonged postoperative mechanical allodynia and inhibited microglial activation in the spinal cord. Conversely, mimicking this increase in C/EBPβ promoted microglial activation via pretreatment with a pre-injection of AAV5-C/EBPβ, leading to prolongation of postsurgical pain. Overall, these results suggested that spinal microglia may play key roles in prolongation of postsurgical pain induced by pre-operative stress and that C/EBPβ may be a potential target for disease treatment.
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Affiliation(s)
- Ming Jiang
- Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Yulin Huang
- 66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Lijun Hu
- 66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Hao Wu
- 66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Yue Liu
- Department of Anesthesiology66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Kun Ni
- Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Xiaokun Zhang
- 66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Yu'e Sun
- 66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Xiaoping Gu
- Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
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42
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Pregnane X receptor (PXR) represses osteoblast differentiation through repression of the Hedgehog signaling pathway. Exp Cell Res 2022; 416:113156. [PMID: 35421365 DOI: 10.1016/j.yexcr.2022.113156] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 04/02/2022] [Accepted: 04/08/2022] [Indexed: 12/14/2022]
Abstract
The pregnane X receptor (PXR, NR1I2) belongs to the nuclear receptor family and functions as a xenobiotic and endobiotic sensor by binding to various molecules through its relatively flexible ligand-binding domain. In addition to these well-known canonical roles, we previously reported that PXR represses osteoblast differentiation. However, the mechanisms underlying the PXR-mediated repression of osteoblast differentiation remains unknown. In this study, we analyzed the changes in global gene expression profiles induced by PXR in calvarial osteoblasts cultured in standard fetal bovine serum (in which PXR induces repression of differentiation), and in those cultured in charcoal-stripped fetal bovine serum (in which PXR does not induce repression of differentiation). The comparison revealed that PXR attenuated the Hedgehog-mediated signaling in culture conditions that induced PXR-mediated repression of differentiation. Real-time PCR analysis showed that PXR repressed the Hedgehog signaling-induced genes such as Gli1 and Hhip, and conversely induced the Hedgehog signaling-repressed genes such as Cdon, Boc, and Gas1. Activation of Smo-mediated signaling in osteoblasts following treatment with a Smo agonist (SAG) significantly restored Gli-mediated transcriptional activity and osteoblast differentiation. Our results demonstrate the osteoblast-autonomous effects of PXR and identify a novel regulation of Hedgehog signaling by nuclear receptors.
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43
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Berthou F, Sobolewski C, Abegg D, Fournier M, Maeder C, Dolicka D, Correia de Sousa M, Adibekian A, Foti M. Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk. Int J Mol Sci 2022; 23:ijms23073959. [PMID: 35409319 PMCID: PMC8999584 DOI: 10.3390/ijms23073959] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/25/2022] [Accepted: 03/31/2022] [Indexed: 11/16/2022] Open
Abstract
Liver-derived circulating factors deeply affect the metabolism of distal organs. Herein, we took advantage of the hepatocyte-specific PTEN knockout mice (LPTENKO), a model of hepatic steatosis associated with increased muscle insulin sensitivity and decreased adiposity, to identify potential secreted hepatic factors improving metabolic homeostasis. Our results indicated that protein factors, rather than specific metabolites, released by PTEN-deficient hepatocytes trigger an improved muscle insulin sensitivity and a decreased adiposity in LPTENKO. In this regard, a proteomic analysis of conditioned media from PTEN-deficient primary hepatocytes identified seven hepatokines whose expression/secretion was deregulated. Distinct expression patterns of these hepatokines were observed in hepatic tissues from human/mouse with NAFLD. The expression of specific factors was regulated by the PTEN/PI3K, PPAR or AMPK signaling pathways and/or modulated by classical antidiabetic drugs. Finally, loss-of-function studies identified FGF21 and the triad AHSG, ANGPTL4 and LECT2 as key regulators of insulin sensitivity in muscle cells and in adipocytes biogenesis, respectively. These data indicate that hepatic PTEN deficiency and steatosis alter the expression/secretion of hepatokines regulating insulin sensitivity in muscles and the lipid metabolism in adipose tissue. These hepatokines could represent potential therapeutic targets to treat obesity and insulin resistance.
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Affiliation(s)
- Flavien Berthou
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Cyril Sobolewski
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Daniel Abegg
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA; (D.A.); (A.A.)
| | - Margot Fournier
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Christine Maeder
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Dobrochna Dolicka
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Marta Correia de Sousa
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Alexander Adibekian
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA; (D.A.); (A.A.)
| | - Michelangelo Foti
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
- Diabetes Center, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
- Correspondence: ; Tel.: +41-(22)-379-52-04
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44
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Sekar M, Thirumurugan K. Autophagy: a molecular switch to regulate adipogenesis and lipolysis. Mol Cell Biochem 2022; 477:727-742. [PMID: 35022960 DOI: 10.1007/s11010-021-04324-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 12/01/2021] [Indexed: 12/16/2022]
Abstract
Obesity is a complex epidemic disease caused by an imbalance of adipose tissue function that results in hyperglycemia, hyperlipidemia and insulin resistance which further develop into type 2 diabetes, cardiovascular disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Adipose tissue is responsible for fat storage; white adipose tissue stores excess energy as fat for availability during starvation, whereas brown adipose tissue regulates thermogenesis through fat oxidation using uncoupling protein 1. However, hypertrophic fat storage results in inflammation and increase the chances for obesity which triggers autophagy genes and lipolytic enzymes to regulate lipid metabolism. Autophagy degrades cargo molecule with the help of lysosome and redistributes the energy back to the cell. Autophagy regulates adipocyte differentiation by modulating master regulators of adipogenesis. Adipogenesis is the process which stores excessive energy in the form of lipid droplets. Lipid droplets (LD) are dynamic cellular organelles that store toxic free-fatty acids into neutral triglycerides in adipose tissue. LD activates both lipolysis and lipophagy to degrade excess triglycerides. In obese tissue, autophagy is activated via pro-inflammatory cytokines produced by surplus fat stored in the adipose tissue. This review focused on the process of autophagy and adipogenesis and the transcription factors that regulate lipogenesis and lipolysis in the adipose tissue. We have also discussed about the importance of autophagic regulation within adipose tissue which controls the onset of obesity and its associated diseases.
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Affiliation(s)
- Mouliganesh Sekar
- Structural Biology Lab, Centre for Biomedical Research, School of Biosciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Kavitha Thirumurugan
- Structural Biology Lab, Centre for Biomedical Research, School of Biosciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
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45
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Dinda B, Dinda M. Natural Products, a Potential Source of New Drugs Discovery to Combat Obesity and Diabetes: Their Efficacy and Multi-targets Actions in Treatment of These Diseases. NATURAL PRODUCTS IN OBESITY AND DIABETES 2022:101-275. [DOI: 10.1007/978-3-030-92196-5_4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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46
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Khushboo, Dubey KK. Microbial metabolites beneficial in regulation of obesity. CURRENT DEVELOPMENTS IN BIOTECHNOLOGY AND BIOENGINEERING 2022:355-375. [DOI: 10.1016/b978-0-12-823506-5.00006-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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47
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Cui S, Li X, Li R, Zhang H, Wang Y, Li Y, Zhu J, Li Z, Lin Y. FGF1 promotes the differentiation of goat intramuscular and subcutaneous preadipocytes. Anim Biotechnol 2021:1-13. [PMID: 34939903 DOI: 10.1080/10495398.2021.2016430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Fibroblast growth factor 1(FGF1) has been proved to bind to specific signal molecules and activate intracellular signal transduction, leading to proliferation or differentiation of cells. However, the role of FGF1 in goat adipocytes is still unclear. Here, we investigated its role in lipogenesis of goats, which depends on the activation of FGFRs. In goat intramuscular and subcutaneous adipocytes, we observed that adipocytes accumulation was inhibited by interfering of FGF1, the expression of C/EBPα, C/EBPβ, LPL, Pref-1, PPARγ, AP2, KLF4, KLF6, KLF10 and KLF17 were significantly down-regulated (p < 0.05). When the FGF1 was up-regulated, the opposite result was found, while the expression of C/EBPβ, LPL, PPARγ, SREBP1, AP2, KLF4, KLF7, KLF15, KLF16 and KLF17 were increased significantly (p < 0.05) in goat intramuscular and subcutaneous adipocytes. The expression level of FGFR1 was significantly and decreased with the interference of FGF1, and increased with the overexpression of FGF1. But in goat subcutaneous adipocytes, only the expression of FGFR2 was consistent with the expression of FGF1. Interference methods confirmed that FGFR1 or FGFR2 and FGF1 have the similarly promoting function in adipocytes differentiation. With the co-transfection technology, we confirmed that FGF1 promoted the differentiation of intramuscular and subcutaneous adipocytes might via FGFR1 or FGFR2, respectively.
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Affiliation(s)
- Sheng Cui
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Xin Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Ruiwen Li
- Reproductive and Endocrine Laboratory, Chengdu Woman-Child Central Hospital, Chengdu, China
| | - Hao Zhang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Yong Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Yanyan Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Jiangjiang Zhu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China
| | - Zhixiong Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Yaqiu Lin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
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48
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Lactobacillus plantarum K8-based paraprobiotics suppress lipid accumulation during adipogenesis by the regulation of JAK/STAT and AMPK signaling pathways. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104824] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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49
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Yap C, Mieremet A, de Vries CJ, Micha D, de Waard V. Six Shades of Vascular Smooth Muscle Cells Illuminated by KLF4 (Krüppel-Like Factor 4). Arterioscler Thromb Vasc Biol 2021; 41:2693-2707. [PMID: 34470477 PMCID: PMC8545254 DOI: 10.1161/atvbaha.121.316600] [Citation(s) in RCA: 158] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/20/2021] [Indexed: 12/23/2022]
Abstract
Multiple layers of vascular smooth muscle cells (vSMCs) are present in blood vessels forming the media of the vessel wall. vSMCs provide a vessel wall structure, enabling it to contract and relax, thus modulating blood flow. They also play a crucial role in the development of vascular diseases, such as atherosclerosis and aortic aneurysm formation. vSMCs display a remarkable high degree of plasticity. At present, the number of different vSMC phenotypes has only partially been characterized. By mapping vSMC phenotypes in detail and identifying triggers for phenotype switching, the relevance of the different phenotypes in vascular disease may be identified. Up until recently, vSMCs were classified as either contractile or dedifferentiated (ie, synthetic). However, single-cell RNA sequencing studies revealed such dedifferentiated arterial vSMCs to be highly diverse. Currently, no consensus exist about the number of vSMC phenotypes. Therefore, we reviewed the data from relevant single-cell RNA sequencing studies, and classified a total of 6 vSMC phenotypes. The central dedifferentiated vSMC type that we classified is the mesenchymal-like phenotype. Mesenchymal-like vSMCs subsequently seem to differentiate into fibroblast-like, macrophage-like, osteogenic-like, and adipocyte-like vSMCs, which contribute differentially to vascular disease. This phenotype switching between vSMCs requires the transcription factor KLF4 (Kruppel-like factor 4). Here, we performed an integrated analysis of the data about the recently identified vSMC phenotypes, their associated gene expression profiles, and previous vSMC knowledge to better understand the role of vSMC phenotype transitions in vascular pathology.
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Affiliation(s)
- Carmen Yap
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Location Academic Medical Center, The Netherlands (C.Y., A.M., C.J.M.d.V., V.d.W.)
| | - Arnout Mieremet
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Location Academic Medical Center, The Netherlands (C.Y., A.M., C.J.M.d.V., V.d.W.)
| | - Carlie J.M. de Vries
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Location Academic Medical Center, The Netherlands (C.Y., A.M., C.J.M.d.V., V.d.W.)
| | - Dimitra Micha
- Department of Clinical Genetics, Amsterdam Cardiovascular Sciences, Vrije Universiteit Amsterdam, Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands (D.M.)
| | - Vivian de Waard
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Location Academic Medical Center, The Netherlands (C.Y., A.M., C.J.M.d.V., V.d.W.)
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50
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Xu Q, Li Y, Lin S, Wang Y, Zhu J, Lin Y. KLF4 Inhibits the Differentiation of Goat Intramuscular Preadipocytes Through Targeting C/EBPβ Directly. Front Genet 2021; 12:663759. [PMID: 34421986 PMCID: PMC8373462 DOI: 10.3389/fgene.2021.663759] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/06/2021] [Indexed: 12/19/2022] Open
Abstract
Intramuscular fat (IMF) deposition is a complicated process, and most of the underlying regulators of this biological process are unknown. Here, we cloned the intact CDS of KLF4 gene, investigated the role of KLF4 by gaining or losing function in vitro and further explored the pathways of KLF4 regulating differentiation of intramuscular preadipocytes in goat. Our results show that goat KLF4 gene consists of 1,536 bp encoding a protein of 486 amino acids. The expression of KLF4 is higher in the lung while lower in the heart and muscle in goat. Knockdown of KLF4 mediated by siRNA technique significantly promotes intramuscular preadipocyte lipid accumulation and upregulates mRNA expression of adipogenic related genes including C/EBPα, C/EBPβ, and PPARγ in vivo cultured cells. Consistently, overexpression of KLF4 inhibits intramuscular adipocyte lipid accumulation and significantly downregulation gene expression of C/EBPβ, PPARγ, aP2, and Pref-1. Further, we found that other members of KLFs were upregulated or downregulated after interference or overexpression of KLF4, including KLF2 and KLF5-7. We also found that C/EBPβ was a potential target of KLF4, because it had an opposite expression pattern with KLF4 during the differentiation of intramuscular preadipocytes and had putative binding sites of KLF4. The dual-luciferase reporter assay indicated that overexpression of KLF4 inhibited the transcriptional activity of C/EBPβ. These results demonstrate that KLF4 inhibits the differentiation of intramuscular preadipocytes in goat by targeting C/EBPβ.
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Affiliation(s)
- Qing Xu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Yanyan Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Sen Lin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China
| | - Yong Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Jiangjiang Zhu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China
| | - Yaqiu Lin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China.,Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, China
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