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Potts CM, Yang X, Lynes MD, Malka K, Liaw L. Exploration of Conserved Human Adipose Subpopulations Using Targeted Single-Nuclei RNA Sequencing Data Sets. J Am Heart Assoc 2025; 14:e038465. [PMID: 40094187 DOI: 10.1161/jaha.124.038465] [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: 08/21/2024] [Accepted: 02/14/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Smooth-muscle cells and pericytes are mural cells. Pericytes can differentiate into myofibroblasts, chondrocytes, vascular smooth-muscle cells, and adipocytes, marking them as a distinct progenitor population. Our goal was to molecularly define the progenitor cell populations in human adipose tissues and test the adipogenic potential of human mural cells. METHODS We used informatic analysis of single-cell RNA sequencing data from human tissues to identify and define pericytes and adipose progenitor cells found in human adipose tissues, including perivascular, brown, and white adipose tissues. RESULTS We established tissue-specific patterns of gene expression in pericytes and other putative human adipocyte progenitor cells. PPARG-expressing pericytes were present in multiple human adipose depots with consistent expression of COL25A1, MYO1B, and POSTN. We also found evidence of tissue-specific pericyte markers. Although there is some conservation between human and mouse adipose tissues, human pericyte populations have unique, depot-specific gene expression signatures. Immunofluorescence staining of human adipose tissue revealed the presence of pericytes both distant from and adjacent to vasculature in human adipose tissue. Additionally, we demonstrated the potential of human brain pericytes and aortic vascular smooth-muscle cells to differentiate into adipocytes in vitro on the basis of intracellular lipid accumulation and expression of adipocyte markers. CONCLUSIONS Human adipose cell populations are distinct from mice, and the pericyte subpopulation in human adipose tissues are present across adipose depots. Given that vascular mural cells, including pericytes and smooth-muscle cells, can undergo adipogenesis, we postulate that they are a novel source of adipocytes in the vascular microenvironment.
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Affiliation(s)
| | - Xuehui Yang
- MaineHealth Institute for Research Scarborough ME
| | | | | | - Lucy Liaw
- MaineHealth Institute for Research Scarborough ME
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2
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Zeng S, Li Z, Li X, Du Q, Zhang Y, Zhong Z, Wang H, Zhang S, Li P, Li H, Chen L, Jiang A, Shang P, Li M, Long K. Inhibition of triglyceride metabolism-associated enhancers alters lipid deposition during adipocyte differentiation. FASEB J 2025; 39:e70347. [PMID: 39873971 PMCID: PMC11774232 DOI: 10.1096/fj.202401137r] [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: 05/22/2024] [Revised: 12/28/2024] [Accepted: 01/09/2025] [Indexed: 01/30/2025]
Abstract
Triglyceride (TG) metabolism is a complex and highly coordinated biological process regulated by a series of genes, and its dysregulation can lead to the occurrence of disorders in lipid metabolism. However, the transcriptional regulatory mechanisms of crucial genes in TG metabolism mediated by enhancer-promoter interactions remain elusive. Here, we identified candidate enhancers regulating the Agpat2, Dgat1, Dgat2, Pnpla2, and Lipe genes in 3T3-L1 adipocytes by integrating epigenomic data (H3K27ac, H3K4me1, and DHS-seq) with chromatin three-dimensional interaction data. Luciferase reporter assays revealed that 11 enhancers exhibited fluorescence activity. The repression of enhancers using the dCas9-KRAB system revealed the functional roles of enhancers of Dgat2 and Pnpla2 in regulating their expression and TG metabolism. Furthermore, transcriptome analyses revealed that inhibition of Dgat2-En4 downregulated pathways associated with lipid metabolism, lipid biosynthesis, and adipocyte differentiation. Additionally, overexpression and motif mutation experiments of transcription factor found that two TFs, PPARG and RXRA, regulate the activity of Agpat2-En1, Dgat2-En4, and Pnpla2-En5. Our study identified functional enhancers regulating TG metabolism and elucidated potential regulatory mechanisms of TG deposition from enhancer-promoter interactions, providing insights into understanding lipid deposition.
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Affiliation(s)
- Sha Zeng
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Ziqi Li
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Xiaokai Li
- Chongqing Academy of Animal SciencesChongqingChina
- National Center of Technology Innovation for PigsChongqingChina
| | - Qinjiao Du
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Yu Zhang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Zhining Zhong
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Haoming Wang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Songling Zhang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Penghao Li
- Jinxin Research Institute for Reproductive Medicine and GeneticsSichuan Jinxin Xi'nan Women's and Children's HospitalChengduChina
| | - Haohuan Li
- College of Veterinary MedicineSichuan Agricultural UniversityChengduChina
| | - Li Chen
- Chongqing Academy of Animal SciencesChongqingChina
- National Center of Technology Innovation for PigsChongqingChina
| | - Anan Jiang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Peng Shang
- Animal Science CollegeTibet Agriculture and Animal Husbandry UniversityLinzhiChina
| | - Mingzhou Li
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Keren Long
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
- Chongqing Academy of Animal SciencesChongqingChina
- National Center of Technology Innovation for PigsChongqingChina
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Li Y, Zheng W, Li X, Lue Z, Liu Y, Wu J, Zhang X. The autophagic regulation of rosiglitazone-promoted adipocyte browning. Front Pharmacol 2024; 15:1412520. [PMID: 38895627 PMCID: PMC11184087 DOI: 10.3389/fphar.2024.1412520] [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: 04/05/2024] [Accepted: 05/14/2024] [Indexed: 06/21/2024] Open
Abstract
Objective: Browning of white adipocytes is considered an efficient approach to combat obesity. Rosiglitazone induces the thermogenetic program of white adipocytes, but the underlying mechanisms remain elusive. Methods: Expression levels of browning and autophagy flux markers were detected by real-time PCR and immunoblotting. H&E and Oil Red O staining were performed to evaluate the lipid droplets area. Nuclear protein extraction and immunoprecipitation were used to detect the proteins interaction. Results: In this study, we reported that rosiglitazone promoted adipocyte browning and inhibited autophagy. Rapamycin, an autophagy inducer, reversed adipocyte browning induced by rosiglitazone. Autophagy inhibition by rosiglitazone does not prevent mitochondrial clearance, which was considered to promote adipose whitening. Instead, autophagy inhibition increased p62 nuclear translocation and stabilized the PPARγ-RXRα heterodimer, which is an essential transcription factor for adipocyte browning. We found that rosiglitazone activated NRF2 in mature adipocytes. Inhibition of NRF2 by ML385 reversed autophagy inhibition and the pro-browning effect of rosiglitazone. Conclusion: Our study linked autophagy inhibition with rosiglitazone-promoted browning of adipocytes and provided a mechanistic insight into the pharmacological effects of rosiglitazone.
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Affiliation(s)
- Yue Li
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou, China
| | - Wanqing Zheng
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou, China
| | - Xinhang Li
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou, China
| | - Zhengwei Lue
- Jinhua Institute of Zhejiang University, Jinhua, China
| | - Yun Liu
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou, China
| | - Jiaying Wu
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Department of Clinical Pharmacy, The First Affliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiangnan Zhang
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou, China
- Jinhua Institute of Zhejiang University, Jinhua, China
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Li X, Zeng S, Chen L, Zhang Y, Li X, Zhang B, Su D, Du Q, Zhang J, Wang H, Zhong Z, Zhang J, Li P, Jiang A, Long K, Li M, Ge L. An intronic enhancer of Cebpa regulates adipocyte differentiation and adipose tissue development via long-range loop formation. Cell Prolif 2024; 57:e13552. [PMID: 37905345 PMCID: PMC10905358 DOI: 10.1111/cpr.13552] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 08/29/2023] [Accepted: 09/11/2023] [Indexed: 11/02/2023] Open
Abstract
Cebpa is a master transcription factor gene for adipogenesis. However, the mechanisms of enhancer-promoter chromatin interactions controlling Cebpa transcriptional regulation during adipogenic differentiation remain largely unknown. To reveal how the three-dimensional structure of Cebpa changes during adipogenesis, we generated high-resolution chromatin interactions of Cebpa in 3T3-L1 preadipocytes and 3T3-L1 adipocytes using circularized chromosome conformation capture sequencing (4C-seq). We revealed dramatic changes in chromatin interactions and chromatin status at interaction sites during adipogenic differentiation. Based on this, we identified five active enhancers of Cebpa in 3T3-L1 adipocytes through epigenomic data and luciferase reporter assays. Next, epigenetic repression of Cebpa-L1-AD-En2 or -En3 by the dCas9-KRAB system significantly down-regulated Cebpa expression and inhibited adipocyte differentiation. Furthermore, experimental depletion of cohesin decreased the interaction intensity between Cebpa-L1-AD-En2 and the Cebpa promoter and down-regulated Cebpa expression, indicating that long-range chromatin loop formation was mediated by cohesin. Two transcription factors, RXRA and PPARG, synergistically regulate the activity of Cebpa-L1-AD-En2. To test whether Cebpa-L1-AD-En2 plays a role in adipose tissue development, we injected dCas9-KRAB-En2 lentivirus into the inguinal white adipose tissue (iWAT) of mice to suppress the activity of Cebpa-L1-AD-En2. Repression of Cebpa-L1-AD-En2 significantly decreased Cebpa expression and adipocyte size, altered iWAT transcriptome, and affected iWAT development. We identified functional enhancers regulating Cebpa expression and clarified the crucial roles of Cebpa-L1-AD-En2 and Cebpa promoter interaction in adipocyte differentiation and adipose tissue development.
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Affiliation(s)
- Xiaokai Li
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Sha Zeng
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Li Chen
- Chongqing Academy of Animal SciencesChongqingChina
- National Center of Technology Innovation for PigsChongqingChina
- Key Laboratory of Pig Industry ScienceMinistry of AgricultureChongqingChina
| | - Yu Zhang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Xuemin Li
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Biwei Zhang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Duo Su
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Qinjiao Du
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Jiaman Zhang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Haoming Wang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Zhining Zhong
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Jinwei Zhang
- Chongqing Academy of Animal SciencesChongqingChina
- National Center of Technology Innovation for PigsChongqingChina
- Key Laboratory of Pig Industry ScienceMinistry of AgricultureChongqingChina
| | - Penghao Li
- Jinxin Research Institute for Reproductive Medicine and GeneticsSichuan Jinxin Xi'nan Women's and Children's HospitalChengduChina
| | - Anan Jiang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Keren Long
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
- Chongqing Academy of Animal SciencesChongqingChina
| | - Mingzhou Li
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- Livestock and Poultry Multi‐omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Liangpeng Ge
- Chongqing Academy of Animal SciencesChongqingChina
- National Center of Technology Innovation for PigsChongqingChina
- Key Laboratory of Pig Industry ScienceMinistry of AgricultureChongqingChina
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Kim NY, Park HM, Lee HP, Hong JT, Yoon DY. (E)-2-Methoxy-4-(3-(4-Methoxyphenyl) Prop-1-en-1-yl) Phenol Suppresses Breast Cancer Progression by Dual-Regulating VEGFR2 and PPARγ. J Microbiol Biotechnol 2024; 34:240-248. [PMID: 37942548 PMCID: PMC10940741 DOI: 10.4014/jmb.2309.09019] [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: 09/14/2023] [Revised: 10/25/2023] [Accepted: 10/26/2023] [Indexed: 11/10/2023]
Abstract
In cancer treatment, multi-target approach has paid attention to a reasonable strategy for the potential agents. We investigated whether (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) could exert an anticancer effect by dual-regulating VEGFR2 and PPARγ. MMPP showed modulating effects in TNBC type (MDA-MB-231 and MDA-MB-468) and luminal A type (MCF7) breast cancer cell lines. MMPP enhanced PPARγ transcriptional activity and inhibited VEGFR2 phosphorylation. MMPP-induced signaling by VEGFR2 and PPARγ ultimately triggered the downregulation of AKT activity. MMPP exhibited anticancer effects, as evidenced by growth inhibition, inducement of apoptosis, and suppression of migration and invasion. At the molecular level, MMPP activated pro-apoptotic proteins (caspase3, caspase8, caspase9, and bax), while inhibiting the anti-apoptotic proteins (bcl2). Additionally, MMPP inhibited the mRNA expressions of EMT-promoting transcription factors. Therefore, our findings showed molecular mechanisms of MMPP by regulating VEGFR2 and PPARγ, and suggested that MMPP has potential to treat breast cancer.
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Affiliation(s)
- Na-Yeon Kim
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| | - Hyo-Min Park
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| | - Hee Pom Lee
- College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Do-Young Yoon
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
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Li Y, Lee W, Zhao ZG, Liu Y, Cui H, Wang HY. Fatty acid binding protein 5 is a novel therapeutic target for hepatocellular carcinoma. World J Clin Oncol 2024; 15:130-144. [PMID: 38292656 PMCID: PMC10823939 DOI: 10.5306/wjco.v15.i1.130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 12/02/2023] [Accepted: 12/25/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide. Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell survival, growth, and evolution. Emerging evidence suggests the importance of fatty acid binding proteins (FABPs) in contribution to cancer progression and metastasis; however, how these FABPs are dysregulated in cancer cells, especially in HCC, and the roles of FABPs in cancer progression have not been well defined. AIM To understand the genetic alterations and expression of FABPs and their associated cancer hallmarks and oncogenes in contributing to cancer malignancies. METHODS We used The Cancer Genome Atlas datasets of pan cancer and liver hepatocellular carcinoma (LIHC) as well as patient cohorts with other cancer types in this study. We investigated genetic alterations of FABPs in various cancer types. mRNA expression was used to determine if FABPs are abnormally expressed in tumor tissues compared to non-tumor controls and to investigate whether their expression correlates with patient clinical outcome, enriched cancer hallmarks and oncogenes previously reported for patients with HCC. We determined the protein levels of FABP5 and its correlated genes in two HCC cell lines and assessed the potential of FABP5 inhibition in treating HCC cells. RESULTS We discovered that a gene cluster including five FABP family members (FABP4, FABP5, FABP8, FABP9 and FABP12) is frequently co-amplified in cancer. Amplification, in fact, is the most common genetic alteration for FABPs, leading to overexpression of FABPs. FABP5 showed the greatest differential mRNA expression comparing tumor with non-tumor tissues. High FABP5 expression correlates well with worse patient outcomes (P < 0.05). FABP5 expression highly correlates with enrichment of G2M checkpoint (r = 0.33, P = 1.1e-10), TP53 signaling pathway (r = 0.22, P = 1.7e-5) and many genes in the gene sets such as CDK1 (r = 0.56, P = 0), CDK4 (r = 0.49, P = 0), and TP53 (r = 0.22, P = 1.6e-5). Furthermore, FABP5 also correlates well with two co-expressed oncogenes PLK1 and BIRC5 in pan cancer especially in LIHC patients (r = 0.58, P = 0; r = 0.58, P = 0; respectively). FABP5high Huh7 cells also expressed higher protein levels of p53, BIRC5, CDK1, CDK2, and CDK4 than FABP5low HepG2 cells. FABP5 inhibition more potently inhibited the tumor cell growth in Huh7 cells than in HepG2 cells. CONCLUSION We discovered that FABP5 gene is frequently amplified in cancer, especially in HCC, leading to its significant elevated expression in HCC. Its high expression correlates well with worse patient outcome, enriched cancer hallmarks and oncogenes in HCC. FABP5 inhibition impaired the cell viability of FABP5high Huh7 cells. All these support that FABP5 is a novel therapeutic target for treating FABP5high HCC.
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Affiliation(s)
- Yan Li
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - William Lee
- Biomedical Engineering, Texas A&M University, College Station, TX 77843, United States
| | - Zhen-Gang Zhao
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - Yi Liu
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - Hao Cui
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - Hao-Yu Wang
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
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Wu X, Yang SY, Zhang YH, Fang JZ, Wang S, Xu ZW, Zhang XJ. Prognostic and immunological roles of heat shock protein A4 in lung adenocarcinoma. World J Clin Oncol 2024; 15:45-61. [PMID: 38292659 PMCID: PMC10823936 DOI: 10.5306/wjco.v15.i1.45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/03/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Heat shock protein A4 (HSPA4) belongs to molecular chaperone protein family which plays important roles within variable cellular activities, including cancer initiation and progression. However, the prognostic and immunological significance of HSPA4 in lung adenocarcinoma (LUAD) has not been revealed yet. AIM To explore the prognostic and immunological roles of HSPA4 to identify a novel prognostic biomarker and therapeutic target for LUAD. METHODS We assessed the prognostic and immunological significance of HSPA4 in LUAD using data from The Cancer Genome Atlas database. The association between HSPA4 expression and clinical-pathological features was assessed through Kruskal-Wallis and Wilcoxon signed-rank test. Univariate/multivariate Cox regression analyses and Kaplan-Meier curves were employed to evaluate prognostic factors, including HSPA4, in LUAD. Gene set enrichment analysis (GSEA) was conducted to identify the key signaling pathways associated with HSPA4. The correlation between HSPA4 expression and cancer immune infiltration was evaluated using single-sample gene set enrichment analysis (ssGSEA). RESULTS Overexpressing HSPA4 was significantly related to advanced pathologic TNM stage, advanced pathologic stage, progression disease status of primary therapy outcome and female subgroups with LUAD. In addition, increased HSPA4 expression was found to be related to worse disease-specific survival and overall survival. GSEA analysis indicated a significant correlation between HSPA4 and cell cycle regulation and immune response, particularly through diminishing the function of cytotoxicity cells and CD8 T cells. The ssGSEA algorithm showed a positive correlation between HSPA4 expression and infiltrating levels of Th2 cells, while a negative correlation was observed with cytotoxic cell infiltration levels. CONCLUSION Our findings indicate HSPA4 is related to prognosis and immune cell infiltrates and may act as a novel prognostic biomarker and therapeutic target for LUAD.
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Affiliation(s)
- Xuan Wu
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Shen-Ying Yang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Yi-Hua Zhang
- Graduate School, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
| | - Jin-Zhou Fang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Shuai Wang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Zhi-Wei Xu
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Xiao-Ju Zhang
- Department of Pulmonary and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
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8
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Tang W, Ding Z, Gao H, Yan Q, Liu J, Han Y, Hou X, Liu Z, Chen L, Yang D, Ma G, Cao H. Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPAR γ/FABP4 signaling in mice. Acta Pharm Sin B 2023; 13:4535-4552. [PMID: 37969743 PMCID: PMC10638509 DOI: 10.1016/j.apsb.2023.07.001] [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] [Received: 02/24/2023] [Revised: 05/14/2023] [Accepted: 05/18/2023] [Indexed: 11/17/2023] Open
Abstract
Osteoporosis (OP) is a systemic skeletal disease that primarily affects the elderly population, which greatly increases the risk of fractures. Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass. Kindlin-2 specific deletion (K2KO) controlled by Adipoq-Cre mice or adipose tissue-targeting AAV (AAV-Rec2-CasRx-sgK2) significantly increases bone mass. Mechanistically, Kindlin-2 promotes peroxisome proliferator-activated receptor gamma (PPARγ) activation and downstream fatty acid binding protein 4 (FABP4) expression through stabilizing fatty acid synthase (FAS), and increased FABP4 inhibits insulin expression and decreases bone mass. Kindlin-2 inhibition results in accelerated FAS degradation, decreased PPARγ activation and FABP4 expression, and therefore increased insulin expression and bone mass. Interestingly, we find that FABP4 is increased while insulin is decreased in serum of OP patients. Increased FABP4 expression through PPARγ activation by rosiglitazone reverses the high bone mass phenotype of K2KO mice. Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice. Collectively, our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.
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Affiliation(s)
- Wanze Tang
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518055, China
| | - Zhen Ding
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
| | - Huanqing Gao
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
| | - Qinnan Yan
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
| | - Jingping Liu
- Clinical Laboratory of the Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Yingying Han
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
| | - Xiaoting Hou
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
| | - Zhengwei Liu
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
| | - Litong Chen
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
| | - Dazhi Yang
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518055, China
| | - Guixing Ma
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
| | - Huiling Cao
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
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9
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Sheng W, Wang Q, Qin H, Cao S, Wei Y, Weng J, Yu F, Zeng H. Osteoarthritis: Role of Peroxisome Proliferator-Activated Receptors. Int J Mol Sci 2023; 24:13137. [PMID: 37685944 PMCID: PMC10487662 DOI: 10.3390/ijms241713137] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/04/2023] [Accepted: 08/15/2023] [Indexed: 09/10/2023] Open
Abstract
Osteoarthritis (OA) represents the foremost degenerative joint disease observed in a clinical context. The escalating issue of population aging significantly exacerbates the prevalence of OA, thereby imposing an immense annual economic burden on societies worldwide. The current therapeutic landscape falls short in offering reliable pharmaceutical interventions and efficient treatment methodologies to tackle this growing problem. However, the scientific community continues to dedicate significant efforts towards advancing OA treatment research. Contemporary studies have discovered that the progression of OA may be slowed through the strategic influence on peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated receptors within the nuclear hormone receptor family. The three distinctive subtypes-PPARα, PPARβ/δ, and PPARγ-find expression across a broad range of cellular terminals, thus managing a multitude of intracellular metabolic operations. The activation of PPARγ and PPARα has been shown to efficaciously modulate the NF-κB signaling pathway, AP-1, and other oxidative stress-responsive signaling conduits, leading to the inhibition of inflammatory responses. Furthermore, the activation of PPARγ and PPARα may confer protection to chondrocytes by exerting control over its autophagic behavior. In summation, both PPARγ and PPARα have emerged as promising potential targets for the development of effective OA treatments.
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Affiliation(s)
- Weibei Sheng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Qichang Wang
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Haotian Qin
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Siyang Cao
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Yihao Wei
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Jian Weng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Fei Yu
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Hui Zeng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
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10
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Kim SP, Seward AH, Garcia-Diaz J, Alekos N, Gould NR, Aja S, Stains JP, Wolfgang MJ, Riddle RC. Peroxisome proliferator activated receptor-γ in osteoblasts controls bone formation and fat mass by regulating sclerostin expression. iScience 2023; 26:106999. [PMID: 37534168 PMCID: PMC10391670 DOI: 10.1016/j.isci.2023.106999] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/01/2023] [Accepted: 05/25/2023] [Indexed: 08/04/2023] Open
Abstract
The nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) is a key contributor to metabolic function via its adipogenic and insulin-sensitizing functions, but it has negative effects on skeletal homeostasis. Here, we questioned whether the skeletal and metabolic actions of PPARγ are linked. Ablating Pparg expression in osteoblasts and osteocytes produced a high bone mass phenotype, secondary to increased osteoblast activity, and a reduction in subcutaneous fat mass because of reduced fatty acid synthesis and increased fat oxidation. The skeletal and metabolic phenotypes in Pparg mutants proceed from the regulation of sclerostin production by PPARγ. Mutants exhibited reductions in skeletal Sost expression and serum sclerostin levels while increasing production normalized both phenotypes. Importantly, disrupting the production of sclerostin synergized with the insulin-sensitizing actions of a PPARγ agonist while preventing bone loss. These data suggest that modulating sclerostin action may prevent bone loss associated with anti-diabetic therapies and augment their metabolic actions.
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Affiliation(s)
- Soohyun P. Kim
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Avery H. Seward
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jean Garcia-Diaz
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Nathalie Alekos
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Nicole R. Gould
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Susan Aja
- Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Joseph P. Stains
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Michael J. Wolfgang
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ryan C. Riddle
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Research and Development Service, Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA
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11
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Vazquez-Sandoval A, Velez-delValle C, Hernández-Mosqueira C, Marsch-Moreno M, Ayala-Sumuano JT, Kuri-Harcuch W. FAM129B is a cooperative protein that regulates adipogenesis. Biochem Biophys Res Commun 2023; 638:66-75. [PMID: 36442234 DOI: 10.1016/j.bbrc.2022.11.042] [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: 10/28/2022] [Revised: 11/08/2022] [Accepted: 11/14/2022] [Indexed: 11/21/2022]
Abstract
FAM129B is one of Niban-like proteins described in neoplastic cells and implicated in melanoma cell invasion, but no reports have been published on FAM129B and cell differentiation. We show that FAM129B is early and transiently expressed and crucial for 3T3-F442A adipogenesis. Fam129b is expressed downstream of the early genes Cebpb, Klf4, Klf5 and Srebf1a, but upstream of Pparg2 since knockdown of Fam129b blocked Pparg2 expression and adipose differentiation. Glycogen synthase kinase 3 beta activity, a crucial kinase for adipogenesis, and the ERK1/2 are involved in FAM129B phosphorylation as part of the adipogenic program. Phosphorylated FAM129B is crucial for Pparg2 expression and the lipogenic gene expression downstream of Pparg2, and hence for adipogenesis. Fam129b knockdown reduced adipocyte cluster formation and size, regulating commitment and clonal amplification. In vivo, BAT, inguinal and epidydimal fat expressed Fam129b, suggesting a role in adipose tissue development. We conclude that FAM129B is a cooperative protein that regulates differentiation during the early stages of adipogenesis.
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Affiliation(s)
- Alfredo Vazquez-Sandoval
- Department of Cell Biology, Center of Research and Advanced Studies (CINVESTAV), IPN Avenida Instituto Politécnico Nacional 2508, Mexico City, CP 07360, Mexico
| | - Cristina Velez-delValle
- Department of Cell Biology, Center of Research and Advanced Studies (CINVESTAV), IPN Avenida Instituto Politécnico Nacional 2508, Mexico City, CP 07360, Mexico
| | - Claudia Hernández-Mosqueira
- Department of Cell Biology, Center of Research and Advanced Studies (CINVESTAV), IPN Avenida Instituto Politécnico Nacional 2508, Mexico City, CP 07360, Mexico
| | - Meytha Marsch-Moreno
- Department of Cell Biology, Center of Research and Advanced Studies (CINVESTAV), IPN Avenida Instituto Politécnico Nacional 2508, Mexico City, CP 07360, Mexico
| | - Jorge-Tonatiuh Ayala-Sumuano
- Department of Cell Biology, Center of Research and Advanced Studies (CINVESTAV), IPN Avenida Instituto Politécnico Nacional 2508, Mexico City, CP 07360, Mexico; Department of Biomedical Research, IDIX Biotech, Avenida de Los Portones 1151, Queretaro, CP 76100, Mexico
| | - Walid Kuri-Harcuch
- Department of Cell Biology, Center of Research and Advanced Studies (CINVESTAV), IPN Avenida Instituto Politécnico Nacional 2508, Mexico City, CP 07360, Mexico.
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12
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Chen J, You R, Lv Y, Liu H, Yang G. Conjugated linoleic acid regulates adipocyte fatty acid binding protein expression via peroxisome proliferator-activated receptor α signaling pathway and increases intramuscular fat content. Front Nutr 2022; 9:1029864. [PMID: 36523338 PMCID: PMC9745092 DOI: 10.3389/fnut.2022.1029864] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/19/2022] [Indexed: 06/22/2024] Open
Abstract
Intramuscular fat (IMF) is correlated positively with meat tenderness, juiciness and taste that affected sensory meat quality. Conjugated linoleic acid (CLA) has been extensively researched to increase IMF content in animals, however, the regulatory mechanism remains unclear. Adipocyte fatty acid binding protein (A-FABP) gene has been proposed as candidates for IMF accretion. The purpose of this study is to explore the molecular regulatory pathways of CLA on intramuscular fat deposition. Here, our results by cell lines indicated that CLA treatment promoted the expression of A-FABP through activated the transcription factor of peroxisome proliferator-activated receptor α (PPARα). Moreover, in an animal model, we discovered that dietary supplemental with CLA significantly enhanced IMF deposition by up-regulating the mRNA and protein expression of PPARα and A-FABP in the muscle tissues of mice. In addition, our current study also demonstrated that dietary CLA increased mRNA expression of genes and enzymes involved in fatty acid synthesis and lipid metabolism the muscle tissues of mice. These findings suggest that CLA mainly increases the expression of A-FABP through PPARα signaling pathway and regulates the expression of genes and enzymes related to IMF deposition, thus increasing IMF content. These results contribute to better understanding the molecular mechanism of IMF accretion in animals for the improvement of meat quality.
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Affiliation(s)
| | | | | | | | - Guoqing Yang
- Laboratory of Animal Gene Engineering, College of Life Sciences, Henan Agricultural University, Zhengzhou, China
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13
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PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation. Nat Commun 2022; 13:7090. [PMID: 36402763 PMCID: PMC9675755 DOI: 10.1038/s41467-022-34766-9] [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] [Received: 03/13/2022] [Accepted: 11/07/2022] [Indexed: 11/21/2022] Open
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ's ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.
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14
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Zheng J, Duan Y, Zheng C, Yu J, Li F, Guo Q, Yin Y. Long-Term Protein Restriction Modulates Lipid Metabolism in White Adipose Tissues and Alters Colonic Microbiota of Shaziling Pigs. Animals (Basel) 2022; 12:ani12212944. [PMID: 36359067 PMCID: PMC9654241 DOI: 10.3390/ani12212944] [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] [Received: 09/08/2022] [Revised: 10/11/2022] [Accepted: 10/21/2022] [Indexed: 12/03/2022] Open
Abstract
Obesity is a matter of concern to the public. Abundant evidence has been accumulated that nutritional intervention is a promising strategy to address this health issue. The objective of this study is to investigate alterations in the lipid metabolism in white adipose tissues and the gut microbiota of Shaziling pigs challenged by long-term protein restriction. Results showed that compared with the control group, reducing the protein level by 20% (−20%) increased the mRNA abundance of FABP4 in white adipose tissues (p < 0.05). This occurred in conjunction with increases in PPARγ protein expression. Conversely, the protein expression of C/EBPα was reduced in the −20% group (p < 0.05). Moreover, the −20% group had increased/decreased phosphorylation of AMPKα/mTOR, respectively (p < 0.05). As for the colonic gut microbiota, a 20% reduction in the protein level led to increased Lachnospiraceae XPB1014 group abundance at the genus level (p < 0.01). Collectively, these results indicated that a 20% protein reduction could modulate lipid metabolism and alter the colonic microbiota of Shaziling pigs, an approach which might be translated into a treatment for obesity.
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Affiliation(s)
- Jie Zheng
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Yehui Duan
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
- Correspondence: (Y.D.); (Y.Y.)
| | - Changbing Zheng
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Jiayi Yu
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Fengna Li
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Qiuping Guo
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Yulong Yin
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
- Correspondence: (Y.D.); (Y.Y.)
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15
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Mobilia M, Whitus C, Karakashian A, Lu HS, Daugherty A, Gordon SM. Dennd5b-Deficient Mice are Resistant to PCSK9-Induced Hypercholesterolemia and Diet-Induced Hepatic Steatosis. J Lipid Res 2022; 63:100296. [PMID: 36243100 PMCID: PMC9685390 DOI: 10.1016/j.jlr.2022.100296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 09/01/2022] [Accepted: 09/10/2022] [Indexed: 11/07/2022] Open
Abstract
Dennd5b plays a pivotal role in intestinal absorption of dietary lipids in mice and is associated with body mass index in humans. This study examined the impact of whole-body Dennd5b deletion on plasma lipid concentrations, atherosclerosis, and hepatic lipid metabolism in mice. Hypercholesterolemia was induced in Dennd5b-/- mice by infection with an adeno-associated virus expressing the proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) gain-of-function mutation (PCSK9D377Y) and feeding a Western diet for 12 weeks. Body weight and plasma lipid concentrations were monitored over 12 weeks, and then aortic atherosclerosis and hepatic lipid content were quantified. Compared to Dennd5b+/+ mice, Dennd5b-/- mice were resistant to diet-induced weight gain and PCSK9-induced hypercholesterolemia. Atherosclerosis quantified by en face analysis and in aortic root sections, revealed significantly smaller lesions in Dennd5b-/- compared to Dennd5b+/+ mice. Additionally, Dennd5b-/- mice had significantly less hepatic lipid content (triglyceride and cholesterol) compared to Dennd5b+/+ mice. To gain insight into the basis for reduced hepatic lipids, quantitative PCR was used to measure mRNA abundance of genes involved in hepatic lipid metabolism. Key genes involved in hepatic lipid metabolism and lipid storage were differentially expressed in Dennd5b-/- liver including Pparg, Cd36, and Pnpla3. These findings demonstrate a significant impact of Dennd5b on plasma and hepatic lipid concentrations and resistance to PCSK9-induced hypercholesterolemia in the absence of Dennd5b.
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Affiliation(s)
- Maura Mobilia
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
| | - Callie Whitus
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
| | | | - Hong S. Lu
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA,Department of Physiology, University of Kentucky, Lexington, KY, USA
| | - Alan Daugherty
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA,Department of Physiology, University of Kentucky, Lexington, KY, USA
| | - Scott M. Gordon
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA,Department of Physiology, University of Kentucky, Lexington, KY, USA,For correspondence: Scott M. Gordon
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16
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Zhang L, Ma J, Pan X, Zhang M, Huang W, Liu Y, Yang H, Cheng Z, Zhang G, Qie M, Tong N. LncRNA MIR99AHG enhances adipocyte differentiation by targeting miR-29b-3p to upregulate PPARγ. Mol Cell Endocrinol 2022; 550:111648. [PMID: 35430304 DOI: 10.1016/j.mce.2022.111648] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/16/2022] [Accepted: 04/11/2022] [Indexed: 11/18/2022]
Abstract
AIM The aim is to identify new long noncoding RNAs (lncRNAs) involved in adipocyte differentiation. METHODS High-throughput RNA sequencing of 3T3-L1 preadipocytes was carried out before and after differentiation to identify the target lncRNAs and miRNAs. The effects of lncRNA, miRNA and the network mechanism on adipocyte differentiation were evaluated in vitro and in vivo. Visceral adipose tissue (VAT) was collected from Chinese subjects with obesity or a normal body mass index (BMI), and the levels of lncRNAs, adipogenic genes and miRNAs were measured. RESULTS MIR99AHG, miR-29b-3p were selected as the target lncRNA and miRNA. Short hairpin RNA against MIR99AHG inhibited the differentiation of 3T3-L1 preadipocytes, reduced the expression of the peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer-binding protein alpha (C/EBPα) and fatty acid binding protein 4 (FABP4) genes, upregulated the expression of miR-29b-3p. Overexpression of MIR99AHG showed the opposite effects. Overexpression of miR-29b-3p inhibited the differentiation of 3T3-L1 preadipocytes and decreased the PPARγ level, while inhibition of miR-29b-3p showed the opposite effects. MIR99AHG and PPARγ competed for binding to miR-29b-3p. In mice with high-fat diet-induced obesity, MIR99AHG and miR-29b-3p mRNA level were increased and decreased, respectively. Tail vein injection of adeno-associated virus 9-MIR99AHG-RNA interference (AAV9-MIR99AHG-RNAi) reduced the body weight, epididymal fat mass, MIR99AHG level and increased the expression of miR-29b-3p. The expression levels of MIR99AHG, PPARγ, C/EBPα and FABP4 in human visceral adipose tissue were higher in the obese group than in the normal weight group. CONCLUSIONS MIR99AHG enhances adipogenesis by regulating miR-29b-3p and PPARγ, providing a new target for therapeutic intervention in obesity.
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Affiliation(s)
- Lin Zhang
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China; Laboratory of Diabetes and Islet Transplantation Research, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China
| | - Jinfang Ma
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China; Laboratory of Diabetes and Islet Transplantation Research, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaohui Pan
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China; Laboratory of Diabetes and Islet Transplantation Research, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China
| | - Mei Zhang
- Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Wei Huang
- Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yanjun Liu
- Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, China
| | - Huawu Yang
- Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, China
| | - Zhong Cheng
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Guixiang Zhang
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Mingrong Qie
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Nanwei Tong
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China; Laboratory of Diabetes and Islet Transplantation Research, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China.
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17
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Wang C, Zhang X, Luo L, Luo Y, Wu D, Spilca D, Le Q, Yang X, Alvarez K, Hines WC, Yang XO, Liu M. COX-2 Deficiency Promotes White Adipogenesis via PGE2-Mediated Paracrine Mechanism and Exacerbates Diet-Induced Obesity. Cells 2022; 11:1819. [PMID: 35681514 PMCID: PMC9180646 DOI: 10.3390/cells11111819] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/25/2022] [Accepted: 05/31/2022] [Indexed: 02/01/2023] Open
Abstract
Cyclooxygenase-2 (COX-2) plays a critical role in regulating innate immunity and metabolism by producing prostaglandins (PGs) and other lipid mediators. However, the implication of adipose COX-2 in obesity remains largely unknown. Using adipocyte-specific COX-2 knockout (KO) mice, we showed that depleting COX-2 in adipocytes promoted white adipose tissue development accompanied with increased size and number of adipocytes and predisposed diet-induced adiposity, obesity, and insulin resistance. The increased size and number of adipocytes by COX-2 KO were reversed by the treatment of prostaglandin E2 (PGE2) but not PGI2 and PGD2 during adipocyte differentiation. PGE2 suppresses PPARγ expression through the PKA pathway at the early phase of adipogenesis, and treatment of PGE2 or PKA activator isoproterenol diminished the increased lipid droplets in size and number in COX-2 KO primary adipocytes. Administration of PGE2 attenuated increased fat mass and fat percentage in COX-2 deficient mice. Taken together, our study demonstrated the suppressing effect of adipocyte COX-2 on adipogenesis and reveals that COX-2 restrains adipose tissue expansion via the PGE2-mediated paracrine mechanism and prevents the development of obesity and related metabolic disorders.
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Affiliation(s)
- Chunqing Wang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (C.W.); (X.Z.); (L.L.); (Y.L.); (D.S.); (Q.L.); (X.Y.); (K.A.); (W.C.H.)
| | - Xing Zhang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (C.W.); (X.Z.); (L.L.); (Y.L.); (D.S.); (Q.L.); (X.Y.); (K.A.); (W.C.H.)
| | - Liping Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (C.W.); (X.Z.); (L.L.); (Y.L.); (D.S.); (Q.L.); (X.Y.); (K.A.); (W.C.H.)
| | - Yan Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (C.W.); (X.Z.); (L.L.); (Y.L.); (D.S.); (Q.L.); (X.Y.); (K.A.); (W.C.H.)
| | - Dandan Wu
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (D.W.); (X.O.Y.)
| | - Dianna Spilca
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (C.W.); (X.Z.); (L.L.); (Y.L.); (D.S.); (Q.L.); (X.Y.); (K.A.); (W.C.H.)
| | - Que Le
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (C.W.); (X.Z.); (L.L.); (Y.L.); (D.S.); (Q.L.); (X.Y.); (K.A.); (W.C.H.)
| | - Xin Yang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (C.W.); (X.Z.); (L.L.); (Y.L.); (D.S.); (Q.L.); (X.Y.); (K.A.); (W.C.H.)
| | - Katelyn Alvarez
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (C.W.); (X.Z.); (L.L.); (Y.L.); (D.S.); (Q.L.); (X.Y.); (K.A.); (W.C.H.)
| | - William Curtis Hines
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (C.W.); (X.Z.); (L.L.); (Y.L.); (D.S.); (Q.L.); (X.Y.); (K.A.); (W.C.H.)
| | - Xuexian O. Yang
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (D.W.); (X.O.Y.)
- Autophagy Inflammation and Metabolism Center for Biomedical Research Excellence, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (C.W.); (X.Z.); (L.L.); (Y.L.); (D.S.); (Q.L.); (X.Y.); (K.A.); (W.C.H.)
- Autophagy Inflammation and Metabolism Center for Biomedical Research Excellence, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
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18
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Huang CJ, Choo KB, Chen CF. The MicroRNA-Signaling-Peroxisome Proliferator-Activated Receptor Gamma Connection in the Modulation of Adipogenesis: Bioinformatics Projection on Chicken. Poult Sci 2022; 101:101950. [PMID: 35689996 PMCID: PMC9192975 DOI: 10.1016/j.psj.2022.101950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 03/19/2022] [Accepted: 04/15/2022] [Indexed: 10/29/2022] Open
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19
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Kan S, Li R, Tan Y, Yang F, Xu S, Wang L, Zhang L, Sun X, Chen X, Yang Y, Shu W, Wan H, Chen ZF, Liang H, Chen M. Latexin deficiency attenuates adipocyte differentiation and protects mice against obesity and metabolic disorders induced by high-fat diet. Cell Death Dis 2022; 13:175. [PMID: 35210404 PMCID: PMC8873487 DOI: 10.1038/s41419-022-04636-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/14/2022] [Accepted: 02/10/2022] [Indexed: 12/12/2022]
Abstract
AbstractObesity is a risk factor for many chronic diseases, and is associated with increased incidence rate of type 2 diabetes, hypertension, dyslipidemia and cardiovascular diseases. Adipocyte differentiation play critical role during development of obesity. Latexin (LXN), a mammalian carboxypeptidase inhibitor, plays important role in the proliferation and differentiation of stem cells, and highlights as a differentiation-associated gene that was significantly downregulated in prostate stem cells and whose expression increases through differentiation. However, it is unclear whether LXN is involved in adipocyte differentiation. The aim of this study was to evaluate the role of LXN on adipocyte differentiation, as well as its effects on high fat-induced obesity and metabolic disorders. In this study, we determine the expression of LXN in adipose tissue of lean and fat mice by Western blot, qPCR and immunohistochemistry. We found that LXN in fat tissues was continuous increased during the development of diet-induced obesity. We fed wild-type (WT) and LXN−/−mice with high-fat diet (HFD) to study the effects of LXN on obesity and related metabolic functions. We found that mice deficient in LXN showed resistance against high-fat diet (HFD)-induced obesity, glucose tolerance, insulin tolerance and hepatic steatosis. In vitro studies indicated that LXN was highly induced during adipocyte differentiation, and positively regulated adipocyte differentiation and adipogenesis in 3T3-L1 cells and primary preadipocytes. Functional analysis revealed that the expression of LXN was positively regulated by mTOR/RXR/PPARɤ signaling pathway during the differentiation of adipocytes, while LXN deletion decreased the protein level of PPARɤ in adipocyte through enhancing FABP4 mediated ubiquitination, which led to impaired adipocyte differentiation and lipogenesis. Collectively, our data provide evidence that LXN is a key positive regulator of adipocyte differentiation, and therapeutics targeting LXN could be effective in preventing obesity and its associated disorders in clinical settings.
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Potential Prebiotic and Anti-Obesity Effects of Codium fragile Extract. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12030959] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Polysaccharides from marine algae exhibit beneficial biological activities. In this study, we examined the effect of Codium fragile extract (CFE) on prebiotic and anti-obesity activity through in vitro experiments. CFE increases the growth of specific beneficial microbial populations with concomitant decrease in pathogenic microbes. Further, total phenolic content (TPC), total flavonoid content (TFC), and DPPH radical scavenging activity (DPPH activity) after fermentation with CFE as the carbon source were higher than for glucose as the control. Moreover, CFE inhibited adipocyte differentiation by inducing differentiation-related factors when the induction of 3T3-L1 preadipocytes into adipocytes was induced. Therefore, we suggest that CFE can be used as a prebiotic material with an anti-obesity effect for human health.
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21
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Nuclear Receptors in Energy Metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1390:61-82. [DOI: 10.1007/978-3-031-11836-4_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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22
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Batty MJ, Chabrier G, Sheridan A, Gage MC. Metabolic Hormones Modulate Macrophage Inflammatory Responses. Cancers (Basel) 2021; 13:cancers13184661. [PMID: 34572888 PMCID: PMC8467249 DOI: 10.3390/cancers13184661] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/31/2021] [Accepted: 09/13/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Macrophages are a type of immune cell which play an important role in the development of cancer. Obesity increases the risk of cancer and obesity also causes disruption to the normal levels of hormones that are produced to coordinate metabolism. Recent research now shows that these metabolic hormones also play important roles in macrophage immune responses and so through macrophages, disrupted metabolic hormone levels may promote cancer. This review article aims to highlight and summarise these recent findings so that the scientific community may better understand how important this new area of research is, and how these findings can be capitalised on for future scientific studies. Abstract Macrophages are phagocytotic leukocytes that play an important role in the innate immune response and have established roles in metabolic diseases and cancer progression. Increased adiposity in obese individuals leads to dysregulation of many hormones including those whose functions are to coordinate metabolism. Recent evidence suggests additional roles of these metabolic hormones in modulating macrophage inflammatory responses. In this review, we highlight key metabolic hormones and summarise their influence on the inflammatory response of macrophages and consider how, in turn, these hormones may influence the development of different cancer types through the modulation of macrophage functions.
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Lepanto P, Levin-Ferreyra F, Koziol U, Malacrida L, Badano JL. Insights into in vivo adipocyte differentiation through cell-specific labeling in zebrafish. Biol Open 2021; 10:271875. [PMID: 34409430 PMCID: PMC8443861 DOI: 10.1242/bio.058734] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/10/2021] [Indexed: 01/04/2023] Open
Abstract
White adipose tissue hyperplasia has been shown to be crucial for handling excess energy in healthy ways. Though adipogenesis mechanisms have been underscored in vitro, we lack information on how tissue and systemic factors influence the differentiation of new adipocytes. While this could be studied in zebrafish, adipocyte identification currently relies on neutral lipid labeling, thus precluding access to cells in early stages of differentiation. Here we report the generation and analysis of a zebrafish line with the transgene fabp4a(-2.7):EGFPcaax. In vivo confocal microscopy of the pancreatic and abdominal visceral depots of transgenic larvae, revealed the presence of labeled mature adipocytes as well as immature cells in earlier stages of differentiation. Through co-labeling for blood vessels, we observed a close interaction of differentiating adipocytes with endothelial cells through cell protrusions. Finally, we implemented hyperspectral imaging and spectral phasor analysis in Nile Red-labeled transgenic larvae and revealed the lipid metabolic transition towards neutral lipid accumulation of differentiating adipocytes. Altogether our work presents the characterization of a novel adipocyte-specific label in zebrafish and uncovers previously unknown aspects of in vivo adipogenesis. This article has an associated First Person interview with the first author of the paper. Summary: Analysis of the differentiation of adipocytes in vivo through cell-specific labeling in zebrafish, revealed their early interaction with blood vessels as well as early lipid metabolic changes.
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Affiliation(s)
- Paola Lepanto
- Human Molecular Genetics Lab, Institut Pasteur de Montevideo, Montevideo, Mataojo 2020, CP11400, Uruguay
| | - Florencia Levin-Ferreyra
- Human Molecular Genetics Lab, Institut Pasteur de Montevideo, Montevideo, Mataojo 2020, CP11400, Uruguay
| | - Uriel Koziol
- Sección Biología Celular, Facultad de Ciencias, Universidad de la República, Montevideo, Igua 4225, CP11400, Uruguay
| | - Leonel Malacrida
- Advanced Bioimaging Unit, Institut Pasteur de Montevideo and Universidad de la República, Montevideo, Mataojo 2020, CP11400, Uruguay.,Departamento de Fisiopatología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Av. Italia s/n, CP11600, Uruguay
| | - José L Badano
- Human Molecular Genetics Lab, Institut Pasteur de Montevideo, Montevideo, Mataojo 2020, CP11400, Uruguay
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24
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PPAR Gamma and Viral Infections of the Brain. Int J Mol Sci 2021; 22:ijms22168876. [PMID: 34445581 PMCID: PMC8396218 DOI: 10.3390/ijms22168876] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 12/29/2022] Open
Abstract
Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a master regulator of metabolism, adipogenesis, inflammation and cell cycle, and it has been extensively studied in the brain in relation to inflammation or neurodegeneration. Little is known however about its role in viral infections of the brain parenchyma, although they represent the most frequent cause of encephalitis and are a major threat for the developing brain. Specific to viral infections is the ability to subvert signaling pathways of the host cell to ensure virus replication and spreading, as deleterious as the consequences may be for the host. In this respect, the pleiotropic role of PPARγ makes it a critical target of infection. This review aims to provide an update on the role of PPARγ in viral infections of the brain. Recent studies have highlighted the involvement of PPARγ in brain or neural cells infected by immunodeficiency virus 1, Zika virus, or human cytomegalovirus. They have provided a better understanding on PPARγ functions in the infected brain, and revealed that it can be a double-edged sword with respect to inflammation, viral replication, or neuronogenesis. They unraveled new roles of PPARγ in health and disease and could possibly help designing new therapeutic strategies.
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25
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Shi F, Simandi Z, Nagy L, Collins S. Diet-dependent natriuretic peptide receptor C expression in adipose tissue is mediated by PPARγ via long-range distal enhancers. J Biol Chem 2021; 297:100941. [PMID: 34245781 PMCID: PMC8326739 DOI: 10.1016/j.jbc.2021.100941] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/18/2021] [Accepted: 07/06/2021] [Indexed: 02/08/2023] Open
Abstract
The cardiac natriuretic peptides (NPs) are well established as regulators of blood pressure and fluid volume, but they also stimulate adipocyte lipolysis and control the gene program of nonshivering thermogenesis in brown adipose tissue. The NP "clearance" receptor C (NPRC) functions to clear NPs from the circulation via peptide internalization and degradation and thus is an important regulator of NP signaling and adipocyte metabolism. It is well known that the Nprc gene is highly expressed in adipose tissue and dynamically regulated upon nutrition and environmental changes. However, the molecular basis for how Nprc gene expression is regulated is still poorly understood. Here, we identified the nuclear receptor transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) as a transcriptional regulator of Nprc expression in mouse adipocytes. During 3T3-L1 adipocyte differentiation, levels of Nprc expression increase in parallel with PPARγ induction. Rosiglitazone, a classic PPARγ agonist, increases, whereas siRNA knockdown of PPARγ reduces, Nprc expression in 3T3-L1 adipocytes. By using chromosome conformation capture and luciferase reporter assays, we demonstrate that PPARγ controls Nprc gene expression in adipocytes through its long-range distal enhancers. Furthermore, the induction of Nprc expression in adipose tissue during high-fat diet feeding is found to be associated with increased PPARγ enhancer activity. Our findings define PPARγ as a mediator of adipocyte Nprc gene expression and establish a new connection between PPARγ and the control of adipocyte NP signaling in obesity.
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Affiliation(s)
- Fubiao Shi
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Zoltan Simandi
- Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Laszlo Nagy
- Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Johns Hopkins All Children's Hospital, Saint Petersburg, Florida, USA; Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, Saint Petersburg, Florida, USA; Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Sheila Collins
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA; Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
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26
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Donepudi AC, Lee Y, Lee JY, Schuetz JD, Manautou JE. Multidrug resistance-associated protein 4 (Mrp4) is a novel genetic factor in the pathogenesis of obesity and diabetes. FASEB J 2021; 35:e21304. [PMID: 33417247 DOI: 10.1096/fj.202001299rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 12/07/2020] [Accepted: 12/09/2020] [Indexed: 12/21/2022]
Abstract
Multidrug resistance protein 4 (Mrp4) is an efflux transporter known to transport several xenobiotics and endogenous molecules. We recently identified that the lack of Mrp4 increases adipose tissue and body weights in mice. However, the role of Mrp4 in adipose tissue physiology are unknown. The current study aimed at characterizing these specific roles of Mrp4 using wild-type (WT) and knockout (Mrp4-/- ) mice. Our studies determined that Mrp4 is expressed in mouse adipose tissue and that the lack of Mrp4 expression is associated with adipocyte hypertrophy. Furthermore, the lack of Mrp4 increased blood glucose and leptin levels, and impaired glucose tolerance. Additionally, in 3T3-L1 cells and human pre-adipocytes, pharmacological inhibition of Mrp4 increased adipogenesis and altered expression of adipogenic genes. Lack of Mrp4 activity in both of our in vivo and in vitro models leads to increased activation of adipose tissue cAMP response element-binding protein (Creb) and decreased plasma prostaglandin E (PGE) metabolite levels. These changes in Creb activation, coupled with decreased PGE levels, together promoted the observed metabolic phenotype in Mrp4-/- mice. In conclusion, our results indicate that Mrp4 as a novel genetic factor involved in the pathogenesis of metabolic diseases, such as obesity and diabetes.
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Affiliation(s)
- Ajay C Donepudi
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT, USA
| | - Yoojin Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - John D Schuetz
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - José E Manautou
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT, USA
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27
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Rajakumari S, Srivastava S. Aging and β3-adrenergic stimulation alter mitochondrial lipidome of adipose tissue. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:158922. [PMID: 33713833 DOI: 10.1016/j.bbalip.2021.158922] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 02/10/2021] [Accepted: 03/07/2021] [Indexed: 12/14/2022]
Abstract
Mitochondrial abundance and thermogenic capacity are two imperative components that distinguish brown, beige and white adipose tissues. Most importantly, the lipid composition is vital for maintaining the quantity, quality and function of mitochondria. Therefore, we employed quantitative lipidomics to probe the mitochondrial lipidome of adipose tissues. The mitochondrial lipidome reveals β3-adrenergic stimulation and aging drastically altered the levels of phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio and acyl chain desaturation. Precisely, PC36:2 and PE38:4 levels correlate with the increased brown and beige fat activity in young mice. While aging increased lysoPC species in white adipose tissue (WAT) mitochondria, CL-316,243 administration reduced lysoPC species and increased lyso-PE18:1 and 18:2 content during WAT browning. Also, non-thermogenic mitochondria accumulate sphingomyelin (SM), phosphatidylserine (PS), phosphatidic acid (PA) and ether-linked PC (ePC). Similarly, enrichment of phosphatidylglycerol (PG) and cardiolipin (CL) levels are associated with thermogenic mitochondria. Also, our in vitro experiment supports that blocking the de novo sphingolipid synthesis pathway by myriocin, SPT1 inhibitor increased the thermogenic capacity and oxygen consumption rate in mature adipocytes. Overall, our study suggests mitochondria of brown, beige and white adipose tissues own a unique pattern of lipid molecular species and their levels are altered by aging and CL-316,243 administration.
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Affiliation(s)
- Sona Rajakumari
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru 560012, India.
| | - Simran Srivastava
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru 560012, India
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28
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Barrett E, Loverin A, Wang H, Carlson M, Larsen TD, Almeida MM, Whitman J, Baack ML, Joss-Moore LA. Uteroplacental Insufficiency with Hypoxia Upregulates Placental PPARγ-KMT5A Axis in the Rat. Reprod Sci 2021; 28:1476-1488. [PMID: 33398850 PMCID: PMC8215892 DOI: 10.1007/s43032-020-00434-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 12/13/2020] [Indexed: 12/30/2022]
Abstract
The placenta represents a critical node in fetal lipid acquisition, yet the mechanisms by which the placenta handles lipids under normal and pathologic conditions are incompletely understood. A key player in placental lipid handling is peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ influences global gene expression via its regulation of the epigenetic modifier lysine methyltransferase 5A (KMT5A), which places a methyl group on histone 4 lysine 20 (H4K20me) of target genes. Here we test the hypothesis that KMT5A is present in both the human and rat placentas and is affected by uteroplacental insufficiency (UPI) in the rat in association with increased placental lipid accumulation. We assessed levels and localization of KMT5A, as well as lipid droplet accumulation, in human placental tissue collected from maternal donors after delivery by planned cesarean section. Using a rat model of UPI, we also evaluated the effects of UPI on lipid accumulation, PPARγ, KMT5A, and H4K20me in the rat placenta. In this study, we show for the first time the presence and activity of KMT5A, in human and in rat placentas. We also demonstrate that in the rat placenta, UPI increases hypoxia, KMT5a expression, and activity in association with increased lipid accumulation in placenta supporting male fetuses. Placental PPARγ-KMT5A axis may be an important mediator of placental lipid handling.
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Affiliation(s)
- Emily Barrett
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, 84109, USA
| | - Amy Loverin
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, 84109, USA
| | - Haimei Wang
- Department of Pediatrics, University of Utah, 295 Chipeta Way, UT, 84108, Salt Lake City, USA
| | | | - Tricia D Larsen
- Environmental Influences on Health and Disease, Sanford Research, Sioux Falls, SD, 57104, USA
| | - Mariana M Almeida
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Jenna Whitman
- Department of Pediatrics, University of Utah, 295 Chipeta Way, UT, 84108, Salt Lake City, USA
| | - Michelle L Baack
- Environmental Influences on Health and Disease, Sanford Research, Sioux Falls, SD, 57104, USA
| | - Lisa A Joss-Moore
- Department of Pediatrics, University of Utah, 295 Chipeta Way, UT, 84108, Salt Lake City, USA.
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Donsante S, Palmisano B, Serafini M, Robey PG, Corsi A, Riminucci M. From Stem Cells to Bone-Forming Cells. Int J Mol Sci 2021; 22:ijms22083989. [PMID: 33924333 PMCID: PMC8070464 DOI: 10.3390/ijms22083989] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/06/2021] [Accepted: 04/10/2021] [Indexed: 12/22/2022] Open
Abstract
Bone formation starts near the end of the embryonic stage of development and continues throughout life during bone modeling and growth, remodeling, and when needed, regeneration. Bone-forming cells, traditionally termed osteoblasts, produce, assemble, and control the mineralization of the type I collagen-enriched bone matrix while participating in the regulation of other cell processes, such as osteoclastogenesis, and metabolic activities, such as phosphate homeostasis. Osteoblasts are generated by different cohorts of skeletal stem cells that arise from different embryonic specifications, which operate in the pre-natal and/or adult skeleton under the control of multiple regulators. In this review, we briefly define the cellular identity and function of osteoblasts and discuss the main populations of osteoprogenitor cells identified to date. We also provide examples of long-known and recently recognized regulatory pathways and mechanisms involved in the specification of the osteogenic lineage, as assessed by studies on mice models and human genetic skeletal diseases.
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Affiliation(s)
- Samantha Donsante
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina 324, 00161 Rome, Italy; (S.D.); (B.P.); (A.C.)
- Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo, 20900 Monza, Italy;
| | - Biagio Palmisano
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina 324, 00161 Rome, Italy; (S.D.); (B.P.); (A.C.)
| | - Marta Serafini
- Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo, 20900 Monza, Italy;
| | - Pamela G. Robey
- Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA;
| | - Alessandro Corsi
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina 324, 00161 Rome, Italy; (S.D.); (B.P.); (A.C.)
| | - Mara Riminucci
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina 324, 00161 Rome, Italy; (S.D.); (B.P.); (A.C.)
- Correspondence:
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30
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Park JH, Ahn EK, Hwang MH, Park YJ, Cho YR, Ko HJ, Jeong W, Yang SH, Seo DW, Oh JS. Improvement of Obesity and Dyslipidemic Activity of Amomum tsao-ko in C57BL/6 Mice Fed a High-Carbohydrate Diet. Molecules 2021; 26:molecules26061638. [PMID: 33804179 PMCID: PMC7998585 DOI: 10.3390/molecules26061638] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/27/2021] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
Amomum tsao-ko Crevost et Lemaire (Zingiberaceae) is a medicinal herb found in Southeast Asia that is used for the treatment of malaria, abdominal pain, dyspepsia, etc. The aim of this study was to investigate the effect of an ethanol extract of Amomum tsao-ko (EAT) on obesity and hyperlipidemia in C57BL/6 mice fed a high-carbohydrate diet (HCD). First, the mice were divided into five groups (n = 6/group) as follows: normal diet, HCD, and HCD+EAT (100, 200, and 400 mg/kg/day), which were orally administered with EAT daily for 84 days. Using microcomputed tomography (micro-CT) analysis, we found that EAT inhibited not only body-weight gain, but also visceral fat and subcutaneous fat accumulation. Histological analysis confirmed that EAT decreased the size of fat tissues. EAT consistently improved various indices, including plasma levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein, high-density lipoprotein, atherogenic index, and cardiac risk factors, which are related to dyslipidemia—a major risk factor for heart disease. The contents of TC and TG, as well as the lipid droplets of HCD-induced hepatic accumulation in the liver tissue, were suppressed by EAT. Taken together, these findings suggest the possibility of developing EAT as a therapeutic agent for improving HCD-induced obesity and hyperlipidemia.
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Affiliation(s)
- Ju-Hyoung Park
- College of Pharmacy, Dankook University, Dandae-ro 119, Dongnam, Cheonan, Chungnam 31116, Korea; (J.-H.P.); (D.-W.S.)
| | - Eun-Kyung Ahn
- Bio-Center, Gyeonggido Business and Science Accelerator, Gwanggyo-ro 147, Yeoungtong, Suwon, Gyeonggi 16229, Korea; (E.-K.A.); (M.H.H.); (Y.J.P.); (Y.-R.C.); (H.-J.K.); (W.J.)
| | - Min Hee Hwang
- Bio-Center, Gyeonggido Business and Science Accelerator, Gwanggyo-ro 147, Yeoungtong, Suwon, Gyeonggi 16229, Korea; (E.-K.A.); (M.H.H.); (Y.J.P.); (Y.-R.C.); (H.-J.K.); (W.J.)
| | - Young Jin Park
- Bio-Center, Gyeonggido Business and Science Accelerator, Gwanggyo-ro 147, Yeoungtong, Suwon, Gyeonggi 16229, Korea; (E.-K.A.); (M.H.H.); (Y.J.P.); (Y.-R.C.); (H.-J.K.); (W.J.)
| | - Young-Rak Cho
- Bio-Center, Gyeonggido Business and Science Accelerator, Gwanggyo-ro 147, Yeoungtong, Suwon, Gyeonggi 16229, Korea; (E.-K.A.); (M.H.H.); (Y.J.P.); (Y.-R.C.); (H.-J.K.); (W.J.)
| | - Hye-Jin Ko
- Bio-Center, Gyeonggido Business and Science Accelerator, Gwanggyo-ro 147, Yeoungtong, Suwon, Gyeonggi 16229, Korea; (E.-K.A.); (M.H.H.); (Y.J.P.); (Y.-R.C.); (H.-J.K.); (W.J.)
| | - Wonsik Jeong
- Bio-Center, Gyeonggido Business and Science Accelerator, Gwanggyo-ro 147, Yeoungtong, Suwon, Gyeonggi 16229, Korea; (E.-K.A.); (M.H.H.); (Y.J.P.); (Y.-R.C.); (H.-J.K.); (W.J.)
| | - Seung Hwan Yang
- Department of Biotechnology, Chonnam National University, Yeosu, Chonnam 59626, Korea;
| | - Dong-Wan Seo
- College of Pharmacy, Dankook University, Dandae-ro 119, Dongnam, Cheonan, Chungnam 31116, Korea; (J.-H.P.); (D.-W.S.)
| | - Joa Sub Oh
- College of Pharmacy, Dankook University, Dandae-ro 119, Dongnam, Cheonan, Chungnam 31116, Korea; (J.-H.P.); (D.-W.S.)
- Correspondence:
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Hernandez-Quiles M, Broekema MF, Kalkhoven E. PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action. Front Endocrinol (Lausanne) 2021; 12:624112. [PMID: 33716977 PMCID: PMC7953066 DOI: 10.3389/fendo.2021.624112] [Citation(s) in RCA: 242] [Impact Index Per Article: 60.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/08/2021] [Indexed: 12/20/2022] Open
Abstract
The proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is one of the most extensively studied ligand-inducible transcription factors. Since its identification in the early 1990s, PPARγ is best known for its critical role in adipocyte differentiation, maintenance, and function. Emerging evidence indicates that PPARγ is also important for the maturation and function of various immune system-related cell types, such as monocytes/macrophages, dendritic cells, and lymphocytes. Furthermore, PPARγ controls cell proliferation in various other tissues and organs, including colon, breast, prostate, and bladder, and dysregulation of PPARγ signaling is linked to tumor development in these organs. Recent studies have shed new light on PPARγ (dys)function in these three biological settings, showing unified and diverse mechanisms of action. Classical transactivation-where PPARγ activates genes upon binding to PPAR response elements as a heterodimer with RXRα-is important in all three settings, as underscored by natural loss-of-function mutations in FPLD3 and loss- and gain-of-function mutations in tumors. Transrepression-where PPARγ alters gene expression independent of DNA binding-is particularly relevant in immune cells. Interestingly, gene translocations resulting in fusion of PPARγ with other gene products, which are unique to specific carcinomas, present a third mode of action, as they potentially alter PPARγ's target gene profile. Improved understanding of the molecular mechanism underlying PPARγ activity in the complex regulatory networks in metabolism, cancer, and inflammation may help to define novel potential therapeutic strategies for prevention and treatment of obesity, diabetes, or cancer.
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Affiliation(s)
- Miguel Hernandez-Quiles
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Marjoleine F. Broekema
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Eric Kalkhoven
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- *Correspondence: Eric Kalkhoven,
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Scandiffio R, Geddo F, Cottone E, Querio G, Antoniotti S, Gallo MP, Maffei ME, Bovolin P. Protective Effects of ( E)-β-Caryophyllene (BCP) in Chronic Inflammation. Nutrients 2020; 12:nu12113273. [PMID: 33114564 PMCID: PMC7692661 DOI: 10.3390/nu12113273] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/19/2020] [Accepted: 10/21/2020] [Indexed: 12/13/2022] Open
Abstract
(E)-β-caryophyllene (BCP) is a bicyclic sesquiterpene widely distributed in the plant kingdom, where it contributes a unique aroma to essential oils and has a pivotal role in the survival and evolution of higher plants. Recent studies provided evidence for protective roles of BCP in animal cells, highlighting its possible use as a novel therapeutic tool. Experimental results show the ability of BCP to reduce pro-inflammatory mediators such as tumor necrosis factor-alfa (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus ameliorating chronic pathologies characterized by inflammation and oxidative stress, in particular metabolic and neurological diseases. Through the binding to CB2 cannabinoid receptors and the interaction with members of the family of peroxisome proliferator-activated receptors (PPARs), BCP shows beneficial effects on obesity, non-alcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) liver diseases, diabetes, cardiovascular diseases, pain and other nervous system disorders. This review describes the current knowledge on the biosynthesis and natural sources of BCP, and reviews its role and mechanisms of action in different inflammation-related metabolic and neurologic disorders.
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Affiliation(s)
- Rosaria Scandiffio
- Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy; (R.S.); (F.G.); (E.C.); (G.Q.); (S.A.); (M.P.G.)
- Plant Physiology Unit, Department of Life Sciences and Systems Biology, University of Turin, Via Quarello 15/a, 10135 Turin, Italy;
| | - Federica Geddo
- Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy; (R.S.); (F.G.); (E.C.); (G.Q.); (S.A.); (M.P.G.)
| | - Erika Cottone
- Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy; (R.S.); (F.G.); (E.C.); (G.Q.); (S.A.); (M.P.G.)
| | - Giulia Querio
- Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy; (R.S.); (F.G.); (E.C.); (G.Q.); (S.A.); (M.P.G.)
| | - Susanna Antoniotti
- Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy; (R.S.); (F.G.); (E.C.); (G.Q.); (S.A.); (M.P.G.)
| | - Maria Pia Gallo
- Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy; (R.S.); (F.G.); (E.C.); (G.Q.); (S.A.); (M.P.G.)
| | - Massimo E. Maffei
- Plant Physiology Unit, Department of Life Sciences and Systems Biology, University of Turin, Via Quarello 15/a, 10135 Turin, Italy;
| | - Patrizia Bovolin
- Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy; (R.S.); (F.G.); (E.C.); (G.Q.); (S.A.); (M.P.G.)
- Correspondence:
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Liu L, Fan L, Chan M, Kraakman MJ, Yang J, Fan Y, Aaron N, Wan Q, Carrillo-Sepulveda MA, Tall AR, Tabas I, Accili D, Qiang L. PPARγ Deacetylation Confers the Antiatherogenic Effect and Improves Endothelial Function in Diabetes Treatment. Diabetes 2020; 69:1793-1803. [PMID: 32409492 PMCID: PMC7372079 DOI: 10.2337/db20-0217] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 05/11/2020] [Indexed: 12/18/2022]
Abstract
Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes, and tight glycemic control fails to reduce the risk of developing CVD. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor γ (PPARγ) agonists, are potent insulin sensitizers with antiatherogenic properties, but their clinical use is limited by side effects. PPARγ deacetylation on two lysine residues (K268 and K293) induces brown remodeling of white adipose tissue and uncouples the adverse effects of TZDs from insulin sensitization. Here we show that PPARγ deacetylation confers antiatherogenic properties and retains the insulin-sensitizing effects of TZD while circumventing its detriments. We generated mice homozygous with mice with deacetylation-mimetic PPARγ mutations K268R/K293R (2KR) on an LDL-receptor knockout (Ldlr -/- ) background. 2KR:Ldlr -/- mice showed smaller atherosclerotic lesion areas than Ldlr -/- mice, particularly in aortic arches. With rosiglitazone treatment, 2KR:Ldlr -/- mice demonstrated a residual antiatherogenic response and substantial protection against bone loss and fluid retention. The antiatherosclerotic effect of 2KR was attributed to the protection of endothelium, indicated by improved endothelium-dependent vasorelaxation and repressed expression of proatherogenic factors including inducible nitric oxide synthase, interleukin-6, and NADPH oxidase 2. Therefore, manipulating PPARγ acetylation is a promising therapeutic strategy to control risk of CVD in diabetes treatment.
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Affiliation(s)
- Longhua Liu
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Pathology and Cell Biology, Columbia University, New York, NY
| | - Lihong Fan
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Pathology and Cell Biology, Columbia University, New York, NY
- Department of Cardiology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shanxi, China
| | - Michelle Chan
- Department of Biological Sciences, Columbia University, New York, NY
| | - Michael J Kraakman
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Medicine, Columbia University, New York, NY
| | - Jing Yang
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Pathology and Cell Biology, Columbia University, New York, NY
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shanxi, China
| | - Yong Fan
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Pathology and Cell Biology, Columbia University, New York, NY
| | - Nicole Aaron
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Pharmacology, Columbia University, New York, NY
| | - Qianfen Wan
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Pathology and Cell Biology, Columbia University, New York, NY
| | | | - Alan R Tall
- Department of Medicine, Columbia University, New York, NY
| | - Ira Tabas
- Department of Medicine, Columbia University, New York, NY
| | - Domenico Accili
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Medicine, Columbia University, New York, NY
| | - Li Qiang
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Pathology and Cell Biology, Columbia University, New York, NY
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Crivaro A, Bondar C, Mucci JM, Ormazabal M, Feldman RA, Delpino MV, Rozenfeld PA. Gaucher disease-associated alterations in mesenchymal stem cells reduce osteogenesis and favour adipogenesis processes with concomitant increased osteoclastogenesis. Mol Genet Metab 2020; 130:274-282. [PMID: 32536424 DOI: 10.1016/j.ymgme.2020.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/02/2020] [Accepted: 06/02/2020] [Indexed: 01/18/2023]
Abstract
Gaucher disease (GD) is caused by pathogenic mutations in GBA1, the gene that encodes the lysosomal enzyme β-glucocerebrosidase. Until now, treatments for GD cannot completely reverse bone problems. The aim of this work was to evaluate the potential of MSCs from GD patients (GD MSCs) to differentiate towards the osteoblast (GD Ob) and adipocyte (GD Ad) lineages, and their role in osteoclastogenesis. We observed that GD Ob exhibited reduced mineralization, collagen deposition and alkaline phosphatase activity (ALP), as well as decreased gene expression of RUNX2, COLA1 and ALP. We also evaluated the process of osteoclastogenesis and observed that conditioned media from GD MSCs supernatants induced an increase in the number of osteoclasts. In this model, osteoclastogenesis was induced by RANKL and IL-1β. Furthermore, results showed that in GD MSCs there was a promotion in NLRP3 and PPAR-γ gene expression. Adipogenic differentiation revealed that GD Ad had an increase in PPAR-γ and a reduced RUNX2 gene expression, promoting adipocyte differentiation. In conclusion, our results show that GD MSCs exhibited deficient GD Ob differentiation and increased adipogenesis. In addition, we show that GD MSCs promoted increased osteoclastogenesis through RANKL and IL-1β. These changes in GD MSCs are likely to contribute to skeletal imbalance observed in GD patients.
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Affiliation(s)
- A Crivaro
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), Universidad Nacional de La Plata, CONICET, asociado CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, Bv. 120 N(o)1489 (1900), La Plata, Argentina
| | - C Bondar
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), Universidad Nacional de La Plata, CONICET, asociado CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, Bv. 120 N(o)1489 (1900), La Plata, Argentina
| | - J M Mucci
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), Universidad Nacional de La Plata, CONICET, asociado CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, Bv. 120 N(o)1489 (1900), La Plata, Argentina
| | - M Ormazabal
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), Universidad Nacional de La Plata, CONICET, asociado CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, Bv. 120 N(o)1489 (1900), La Plata, Argentina
| | - R A Feldman
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), Hospital de Clínicas "José de San Martín", Facultad de Medicina, CONICET-Universidad de Buenos Aires, Paraguay 2155, (C1121ABG), Buenos Aires, Argentina
| | - M V Delpino
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - P A Rozenfeld
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), Universidad Nacional de La Plata, CONICET, asociado CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, Bv. 120 N(o)1489 (1900), La Plata, Argentina.
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Ambele MA, Dhanraj P, Giles R, Pepper MS. Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways. Int J Mol Sci 2020; 21:E4283. [PMID: 32560163 PMCID: PMC7349855 DOI: 10.3390/ijms21124283] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 06/07/2020] [Indexed: 11/24/2022] Open
Abstract
The formation of adipocytes during embryogenesis has been largely understudied. However, preadipocytes appear to originate from multipotent mesenchymal stromal/stem cells which migrate from the mesoderm to their anatomical localization. Most studies on adipocyte formation (adipogenesis) have used preadipocytes derived from adult stem/stromal cells. Adipogenesis consists of two phases, namely commitment and terminal differentiation. This review discusses the role of signalling pathways, epigenetic modifiers, and transcription factors in preadipocyte commitment and differentiation into mature adipocytes, as well as limitations in our understanding of these processes. To date, a limited number of transcription factors, genes and signalling pathways have been described to regulate preadipocyte commitment. One reason could be that most studies on adipogenesis have used preadipocytes already committed to the adipogenic lineage, which are therefore not suitable for studying preadipocyte commitment. Conversely, over a dozen molecular players including transcription factors, genes, signalling pathways, epigenetic regulators, and microRNAs have been described to be involved in the differentiation of preadipocytes to adipocytes; however, only peroxisome proliferator-activated receptor gamma has proven to be clinically relevant. A detailed understanding of how the molecular players underpinning adipogenesis relate to adipose tissue function could provide new therapeutic approaches for addressing obesity without compromising adipose tissue function.
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Affiliation(s)
- Melvin A. Ambele
- Department of Immunology, and SAMRC Extramural Unit for Stem Cell Research and Therapy, Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (M.A.A.); (P.D.); (R.G.)
- Department of Oral Pathology and Oral Biology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa
| | - Priyanka Dhanraj
- Department of Immunology, and SAMRC Extramural Unit for Stem Cell Research and Therapy, Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (M.A.A.); (P.D.); (R.G.)
| | - Rachel Giles
- Department of Immunology, and SAMRC Extramural Unit for Stem Cell Research and Therapy, Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (M.A.A.); (P.D.); (R.G.)
| | - Michael S. Pepper
- Department of Immunology, and SAMRC Extramural Unit for Stem Cell Research and Therapy, Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (M.A.A.); (P.D.); (R.G.)
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Divakaran SJ, Srivastava S, Jahagirdar A, Rajendran R, Sukhdeo SV, Rajakumari S. Sesaminol induces brown and beige adipocyte formation through suppression of myogenic program. FASEB J 2020; 34:6854-6870. [DOI: 10.1096/fj.201902124r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 02/29/2020] [Accepted: 03/16/2020] [Indexed: 01/12/2023]
Affiliation(s)
- Soumya Jaya Divakaran
- Cardiovascular Diseases and Diabetes Biology Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram India
| | - Simran Srivastava
- Department of Molecular Reproduction, Development and Genetics Indian Institute of Science Bengaluru India
| | - Anusha Jahagirdar
- Cardiovascular Diseases and Diabetes Biology Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram India
| | - Rajprabu Rajendran
- Department of Molecular Reproduction, Development and Genetics Indian Institute of Science Bengaluru India
| | - Shinde Vijay Sukhdeo
- Department of Lipid Science, Lipidomics Center CSIR‐Central Food Technological Research Institute Mysuru India
| | - Sona Rajakumari
- Cardiovascular Diseases and Diabetes Biology Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram India
- Department of Molecular Reproduction, Development and Genetics Indian Institute of Science Bengaluru India
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Trümper V, von Knethen A, Preuß A, Ermilov E, Hackbarth S, Kuchler L, Gunne S, Schäfer A, Bornhütter T, Vereb G, Ujlaky-Nagy L, Brüne B, Röder B, Schindler M, Parnham MJ, Knape T. Flow cytometry-based FRET identifies binding intensities in PPARγ1 protein-protein interactions in living cells. Theranostics 2019; 9:5444-5463. [PMID: 31534496 PMCID: PMC6735382 DOI: 10.7150/thno.29367] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 05/01/2019] [Indexed: 01/10/2023] Open
Abstract
PPARγ is a pharmacological target in inflammatory and metabolic diseases. Upon agonistic treatment or following antagonism, binding of co-factors is altered, which consequently affects PPARγ-dependent transactivation as well as its DNA-independent properties. Therefore, establishing techniques to characterize these interactions is an important issue in living cells. Methods: Using the FRET pair Clover/mRuby2, we set up a flow cytometry-based FRET assay by analyzing PPARγ1 binding to its heterodimerization partner RXRα. Analyses of PPARγ-reporter and co-localization studies by laser-scanning microscopy validated this system. Refining the system, we created a new readout to distinguish strong from weak interactions, focusing on PPARγ-binding to the co-repressor N-CoR2. Results: We observed high FRET in cells expressing Clover-PPARγ1 and mRuby2-RXRα, but no FRET when cells express a mRuby2-RXRα deletion mutant, lacking the PPARγ interaction domain. Focusing on the co-repressor N-CoR2, we identified in HEK293T cells the new splice variant N-CoR2-ΔID1-exon. Overexpressing this isoform tagged with mRuby2, revealed no binding to Clover-PPARγ1, nor in murine J774A.1 macrophages. In HEK293T cells, binding was even lower in comparison to N-CoR2 constructs in which domains established to mediate interaction with PPARγ binding are deleted. These data suggest a possible role of N-CoR2-ΔID1-exon as a dominant negative variant. Because binding to N-CoR2-mRuby2 was not altered following activation or antagonism of Clover-PPARγ1, we determined the effect of pharmacological treatment on FRET intensity. Therefore, we calculated flow cytometry-based FRET efficiencies based on our flow cytometry data. As with PPARγ antagonism, PPARγ agonist treatment did not prevent binding of N-CoR2. Conclusion: Our system allows the close determination of protein-protein interactions with a special focus on binding intensity, allowing this system to characterize the role of protein domains as well as the effect of pharmacological agents on protein-protein interactions.
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Affiliation(s)
- Verena Trümper
- Institute of Biochemistry I - Pathobiochemistry, Faculty of Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Andreas von Knethen
- Institute of Biochemistry I - Pathobiochemistry, Faculty of Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
- Branch for Translational Medicine and Pharmacology, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany
| | - Annegret Preuß
- Department of Physics, Humboldt University Berlin, Newtonstraße 15, 12489 Berlin, Germany
| | - Eugeny Ermilov
- Department of Physics, Humboldt University Berlin, Newtonstraße 15, 12489 Berlin, Germany
| | - Steffen Hackbarth
- Department of Physics, Humboldt University Berlin, Newtonstraße 15, 12489 Berlin, Germany
| | - Laura Kuchler
- Institute of Biochemistry I - Pathobiochemistry, Faculty of Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Sandra Gunne
- Branch for Translational Medicine and Pharmacology, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany
| | - Anne Schäfer
- Institute of Biochemistry I - Pathobiochemistry, Faculty of Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Tobias Bornhütter
- Department of Physics, Humboldt University Berlin, Newtonstraße 15, 12489 Berlin, Germany
| | - György Vereb
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
| | - Lázló Ujlaky-Nagy
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
| | - Bernhard Brüne
- Institute of Biochemistry I - Pathobiochemistry, Faculty of Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
- Branch for Translational Medicine and Pharmacology, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany
| | - Beate Röder
- Department of Physics, Humboldt University Berlin, Newtonstraße 15, 12489 Berlin, Germany
| | - Michael Schindler
- Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Karls University Tübingen, Elfriede-Aulhorn-Str. 6, 72076 Tübingen
| | - Michael J. Parnham
- Branch for Translational Medicine and Pharmacology, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany
| | - Tilo Knape
- Branch for Translational Medicine and Pharmacology, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany
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Al Hasan M, Roy P, Dolan S, Martin PE, Patterson S, Bartholomew C. Adhesion G-protein coupled receptor 56 is required for 3T3-L1 adipogenesis. J Cell Physiol 2019; 235:1601-1614. [PMID: 31304602 DOI: 10.1002/jcp.29079] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 06/14/2019] [Indexed: 12/13/2022]
Abstract
Obesity-associated conditions represent major global health and financial burdens and understanding processes regulating adipogenesis could lead to novel intervention strategies. This study shows that adhesion G-protein coupled receptor 56 (GPR56) gene transcripts are reduced in abdominal visceral white adipose tissue derived from obese Zucker rats versus lean controls. Immunostaining in 3T3-L1 preadipocytes reveals both mitotic cell restricted surface and low level general expression patterns of Gpr56. Gpr56 transcripts are differentially expressed in 3T3-L1 cells during adipogenesis. Transient knockdown (KD) of Gpr56 in 3T3-L1 cells dramatically inhibits differentiation through reducing the accumulation of both neutral cellular lipids (56%) and production of established adipogenesis Pparγ 2 (60-80%), C/ebpα (40-78%) mediator, and Ap2 (56-80%) marker proteins. Furthermore, genome editing of Gpr56 in 3T3-L1 cells created CW2.2.4 and RM4.2.5.5 clones (Gpr56 -/- cells) with compound heterozygous deletion frameshift mutations which abolish adipogenesis. Genome edited cells have sustained levels of the adipogenesis inhibitor β-catenin, reduced proliferation, reduced adhesion, altered profiles, and or abundance of extracellular matrix component gene transcripts for fibronectin, types I, III, and IV collagens and loss of actin stress fibers. β-catenin KD alone is insufficient to restore adipogenesis in Gpr56 -/- cells. Together these data show that Gpr56 is required for adipogenesis in 3T3-L1 cells. This report is the first demonstration that Gpr56 participates in regulation of the adipogenesis developmental program. Modulation of the levels of this protein and/or its biological activity may represent a novel target for development of therapeutic agents for the treatment of obesity.
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Affiliation(s)
- Mohammad Al Hasan
- Department of Biological & Biomedical Sciences, School of Health & Life Sciences, Glasgow Caledonian University, Glasgow, Scotland
| | - Poornima Roy
- Department of Biological & Biomedical Sciences, School of Health & Life Sciences, Glasgow Caledonian University, Glasgow, Scotland
| | - Sharron Dolan
- Department of Biological & Biomedical Sciences, School of Health & Life Sciences, Glasgow Caledonian University, Glasgow, Scotland
| | - Patricia E Martin
- Department of Biological & Biomedical Sciences, School of Health & Life Sciences, Glasgow Caledonian University, Glasgow, Scotland
| | - Steven Patterson
- Department of Biological & Biomedical Sciences, School of Health & Life Sciences, Glasgow Caledonian University, Glasgow, Scotland
| | - Chris Bartholomew
- Department of Biological & Biomedical Sciences, School of Health & Life Sciences, Glasgow Caledonian University, Glasgow, Scotland
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Broekema M, Savage D, Monajemi H, Kalkhoven E. Gene-gene and gene-environment interactions in lipodystrophy: Lessons learned from natural PPARγ mutants. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:715-732. [PMID: 30742913 DOI: 10.1016/j.bbalip.2019.02.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 01/13/2019] [Accepted: 02/02/2019] [Indexed: 12/13/2022]
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Broekema MF, Massink MPG, Donato C, de Ligt J, Schaarschmidt J, Borgman A, Schooneman MG, Melchers D, Gerding MN, Houtman R, Bonvin AMJJ, Majithia AR, Monajemi H, van Haaften GW, Soeters MR, Kalkhoven E. Natural helix 9 mutants of PPARγ differently affect its transcriptional activity. Mol Metab 2019; 20:115-127. [PMID: 30595551 PMCID: PMC6358588 DOI: 10.1016/j.molmet.2018.12.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 12/05/2018] [Accepted: 12/11/2018] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE The nuclear receptor PPARγ is the master regulator of adipocyte differentiation, distribution, and function. In addition, PPARγ induces terminal differentiation of several epithelial cell lineages, including colon epithelia. Loss-of-function mutations in PPARG result in familial partial lipodystrophy subtype 3 (FPDL3), a rare condition characterized by aberrant adipose tissue distribution and severe metabolic complications, including diabetes. Mutations in PPARG have also been reported in sporadic colorectal cancers, but the significance of these mutations is unclear. Studying these natural PPARG mutations provides valuable insights into structure-function relationships in the PPARγ protein. We functionally characterized a novel FPLD3-associated PPARγ L451P mutation in helix 9 of the ligand binding domain (LBD). Interestingly, substitution of the adjacent amino acid K450 was previously reported in a human colon carcinoma cell line. METHODS We performed a detailed side-by-side functional comparison of these two PPARγ mutants. RESULTS PPARγ L451P shows multiple intermolecular defects, including impaired cofactor binding and reduced RXRα heterodimerisation and subsequent DNA binding, but not in DBD-LBD interdomain communication. The K450Q mutant displays none of these functional defects. Other colon cancer-associated PPARγ mutants displayed diverse phenotypes, ranging from complete loss of activity to wildtype activity. CONCLUSIONS Amino acid changes in helix 9 can differently affect LBD integrity and function. In addition, FPLD3-associated PPARγ mutations consistently cause intra- and/or intermolecular defects; colon cancer-associated PPARγ mutations on the other hand may play a role in colon cancer onset and progression, but this is not due to their effects on the most well-studied functional characteristics of PPARγ.
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Affiliation(s)
- Marjoleine F Broekema
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Maarten P G Massink
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Cinzia Donato
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Joep de Ligt
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Joerg Schaarschmidt
- Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, the Netherlands
| | - Anouska Borgman
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Marieke G Schooneman
- Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Diana Melchers
- PamGene International B. V., 's-Hertogenbosch, the Netherlands
| | | | - René Houtman
- PamGene International B. V., 's-Hertogenbosch, the Netherlands
| | - Alexandre M J J Bonvin
- Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, the Netherlands
| | - Amit R Majithia
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Houshang Monajemi
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam, the Netherlands; Rijnstate Hospital, Arnhem, the Netherlands
| | - Gijs W van Haaften
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Maarten R Soeters
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Eric Kalkhoven
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
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Zhang J, Xu X, Liu Y, Zhang L, Odle J, Lin X, Zhu H, Wang X, Liu Y. EPA and DHA Inhibit Myogenesis and Downregulate the Expression of Muscle-related Genes in C2C12 Myoblasts. Genes (Basel) 2019; 10:genes10010064. [PMID: 30669396 PMCID: PMC6356802 DOI: 10.3390/genes10010064] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 01/11/2019] [Indexed: 12/31/2022] Open
Abstract
This study was conducted to elucidate the biological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cell proliferation, differentiation and gene expression in C2C12 myoblasts. C2C12 were treated with various concentrations of EPA or DHA under proliferation and differentiation conditions. Cell viability was analyzed using cell counting kit-8 assays (CCK-8). The Edu assays were performed to analyze cell proliferation. To analyze cell differentiation, the expressions of myogenic marker genes were determined at the transcriptional and translational levels by qRT-PCR, immunoblotting and immunofluorescence. Global gene expression patterns were characterized using RNA-sequencing. Phosphorylation levels of ERK and Akt were examined by immunoblotting. Cell viability and proliferation was significantly inhibited after incubation with EPA (50 and 100 μM) or DHA (100 μM). Both EPA and DHA suppressed C2C12 myoblasts differentiation. RNA-sequencing analysis revealed that some muscle-related genes were significantly downregulated following EPA or DHA (50 μM) treatment, including insulin-like growth factor 2 (IGF-2), troponin T3 (Tnnt3), myoglobin (Mb), myosin light chain phosphorylatable fast skeletal muscle (Mylpf) and myosin heavy polypeptide 3 (Myh3). IGF-2 was crucial for the growth and differentiation of skeletal muscle and could activate the PI3K/Akt and the MAPK/ERK cascade. We found that EPA and DHA (50 μM) decreased the phosphorylation levels of ERK1/2 and Akt in C2C12 myoblasts. Thus, this study suggested that EPA and DHA exerted an inhibitory effect on myoblast proliferation and differentiation and downregulated muscle-related genes expression.
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Affiliation(s)
- Jing Zhang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China.
| | - Xin Xu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China.
| | - Yan Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China.
| | - Lin Zhang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China.
| | - Jack Odle
- Laboratory of Development Nutrition, Department of Animal Science, North Carolina State University, Raleigh, NC 27695, USA.
| | - Xi Lin
- Laboratory of Development Nutrition, Department of Animal Science, North Carolina State University, Raleigh, NC 27695, USA.
| | - Huiling Zhu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China.
| | - Xiuying Wang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China.
| | - Yulan Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China.
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Kagawa Y, Umaru BA, Ariful I, Shil SK, Miyazaki H, Yamamoto Y, Ogata M, Owada Y. Role of FABP7 in tumor cell signaling. Adv Biol Regul 2019; 71:206-218. [PMID: 30245263 DOI: 10.1016/j.jbior.2018.09.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 09/13/2018] [Accepted: 09/13/2018] [Indexed: 06/08/2023]
Abstract
Lipids are major molecules for the function of organisms and are involved in the pathophysiology of various diseases. Fatty acids (FAs) signaling and their metabolism are some of the most important pathways in tumor development, as lipids serve as energetic sources during carcinogenesis. Fatty acid binding proteins (FABPs) facilitate FAs transport to different cell organelles, modulating their metabolism along with mediating other physiological activities. FABP7, brain-typed FABP, is thought to be an important molecule for cell proliferation in healthy as well as diseased organisms. Several studies on human tumors and tumor-derived cell lines put FABP7 in the center of tumorigenesis, and its high expression level has been reported to correlate with poor prognosis in different tumor types. Several types of FABP7-expressing tumors have shown an up-regulation of cell signaling activity, but molecular mechanisms of FABP7 involvement in tumorigenesis still remain elusive. In this review, we focus on the expression and function of FABP7 in different tumors, and possible mechanisms of FABP7 in tumor proliferation and migration.
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Affiliation(s)
- Yoshiteru Kagawa
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Banlanjo A Umaru
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Islam Ariful
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Pharmacy, University of Rajshahi, Rajshahi, Bangladesh
| | - Subrata Kumar Shil
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hirofumi Miyazaki
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yui Yamamoto
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Anatomy, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Masaki Ogata
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Anatomy, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Yuji Owada
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Gao W, Gao Z, Pu S, Dong Y, Xu X, Yang X, Zhang Y, Fang K, Li J, Yu W, Sun N, Hu L, Xu Q, Cheng Z, Gao Y. The Underlying Regulated Mechanisms of Adipose Differentiation and Apoptosis of Breast Cells after Weaning. Curr Protein Pept Sci 2019; 20:696-704. [PMID: 30678617 DOI: 10.2174/1389203720666190124161652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 12/30/2018] [Accepted: 01/14/2019] [Indexed: 11/22/2022]
Abstract
Numerous experimental studies have demonstrated that a series of remodeling processes occurred in the adipose tissue during the weaning, such as differentiation. Fibroblasts in the breast at weaning stage could re-differentiate into mature adipocytes. Many transcriptional factors were involved in these processes, especially the PPARγ, C/EBP, and SREBP1. There is cell apoptosis participating in the breast tissue degeneration and secretory epithelial cells loss during weaning. In addition, hormones, especially the estrogen and pituitary hormone, play a vital role in the whole reproductive processes. In this review, we mainly focus on the underlying regulated mechanisms of differentiation of adipose tissue and apoptosis of breast cell to provide a specific insight into the physiological changes during weaning.
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Affiliation(s)
- Weihang Gao
- College of PIWEI institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Zhao Gao
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
- Administration of Sports of Guangdong Province, Guangzhou, Guangdong, 510105, China
| | - Shuqi Pu
- College of PIWEI institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Yanbin Dong
- College of PIWEI institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Xiaowen Xu
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510405, China
| | - Xingping Yang
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, China
| | - Yuan Zhang
- Administration of Sports of Guangdong Province, Guangzhou, Guangdong, 510105, China
| | - Kui Fang
- Administration of Sports of Guangdong Province, Guangzhou, Guangdong, 510105, China
| | - Jie Li
- Administration of Sports of Guangdong Province, Guangzhou, Guangdong, 510105, China
| | - Weijian Yu
- Administration of Sports of Guangdong Province, Guangzhou, Guangdong, 510105, China
| | - Nannan Sun
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510405, China
| | - Ling Hu
- College of PIWEI institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Qin Xu
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Zhibin Cheng
- College of Animal Science and Technology, Yunnan Agricultural University, Kunming, Yunan, 650201, China
| | - Yong Gao
- College of PIWEI institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
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Yamanishi K, Maeda S, Kuwahara-Otani S, Hashimoto T, Ikubo K, Mukai K, Nakasho K, Gamachi N, El-Darawish Y, Li W, Okuzaki D, Watanabe Y, Yamanishi H, Okamura H, Matsunaga H. Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia. J Transl Med 2018; 16:314. [PMID: 30453990 PMCID: PMC6245626 DOI: 10.1186/s12967-018-1684-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 11/09/2018] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND The cytokine, interleukin-18 (IL-18), was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence suggesting that it has non-immunological effects on physiological functions. We have previously investigated the potential pathophysiological relationship between IL-18 and dyslipidemia, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which were mediated by lipid energy imbalance. Therefore, herein we focused on brown adipocytes (BAs) and brown adipose tissue (BAT) related to energy consumption as non-shivering thermogenesis. METHODS Il18-/- male mice were generated on the C57Bl/6 background, and littermate C57Bl/6 Il18+/+ male mice were used as controls. To reveal the direct effect of IL-18, primary cell cultures derived from both mice were established. Moreover, for molecular analysis, microarray, quantitative reverse transcription PCR and western blotting were performed using 6 and 12 weeks old mice. To evaluate the short- and long-term effects of IL-18 on BAT, recombinant IL-18 was administered for 2 and 12 weeks, respectively. RESULTS Compared with Il18+/+ mice, BAT of Il18-/- mice showed earlier differentiation and lipid accumulation. To examine the direct effect of IL-18 on BAT, BA cell cultures were established. Myogenic factor 5-expressing adipose precursor cells were extracted from Il18+/+ and Il18-/- mice. PR domain containing 16 (PRDM16), a differentiation inducer, was strongly expressed in Il18-/- BAs, and uncoupling protein 1, a thermogenic and differentiation marker, was upregulated, resulting in the promotion of BA differentiation. Moreover, PRDM16-dependent and independent molecules related to BAT function, such as fibroblast growth factor 21, were activated. These findings were confirmed by comparing Il18+/+ and Il18-/- mice at 6 and 12 weeks of age. Additional analyses of the molecular mechanisms influencing the 'Quantity of adipocytes' identified three associated genes, apolipoprotein C3 (Apoc3), insulin-induced gene 1 (Insig1) and vitamin D (1,25-dihydroxyvitamin D3) receptor (Vdr). Intravenous administration of IL-18 not only significantly improved the expression of some of these genes, but it also significantly decreased the adipocytes' size. CONCLUSIONS This study demonstrated the critical function of IL-18 in differentiation and lipid metabolism in BAs. Furthermore, IL-18 may contribute to novel treatments by improving the energy imbalance.
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Affiliation(s)
- Kyosuke Yamanishi
- Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Seishi Maeda
- Department of Anatomy and Cell Biology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Sachi Kuwahara-Otani
- Department of Anatomy and Cell Biology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Takuya Hashimoto
- Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Kaoru Ikubo
- Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Keiichiro Mukai
- Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Keiji Nakasho
- Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Naomi Gamachi
- Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Yosif El-Darawish
- Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Wen Li
- Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Daisuke Okuzaki
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Japan
| | - Yuko Watanabe
- Hirakata General Hospital for Developmental Disorders, 2-1-1 Tsudahigashi, Hirakata, Osaka, 573-0122, Japan
| | - Hiromichi Yamanishi
- Hirakata General Hospital for Developmental Disorders, 2-1-1 Tsudahigashi, Hirakata, Osaka, 573-0122, Japan
| | - Haruki Okamura
- Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hisato Matsunaga
- Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.
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Kim CY, Kim KH. Selenate Prevents Adipogenesis through Induction of Selenoprotein S and Attenuation of Endoplasmic Reticulum Stress. Molecules 2018; 23:molecules23112882. [PMID: 30400605 PMCID: PMC6278472 DOI: 10.3390/molecules23112882] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/01/2018] [Accepted: 11/02/2018] [Indexed: 12/05/2022] Open
Abstract
The conversion of preadipocytes to adipocytes (adipogenesis) is a potential target to treat or prevent obesity. Selenate, an inorganic form of selenium, elicits diverse health benefits, mainly through its incorporation into selenoproteins. The individual roles of selenium and certain selenoproteins have been reported. However, the effects of selenate treatment on selenoproteins in adipocytes are unclear. In this study, the effects of selenate pretreatment on selenoprotein and endoplasmic reticulum (ER) stress during adipogenesis were examined in vitro. The selenate pretreatment dose-dependently suppressed the adipogenesis of 3T3-L1 preadipocytes. The selenate pretreatment at 50 μM for 24 h almost completely suppressed adipogenesis without cytotoxic effects. The expression of the adipogenic genes peroxisome proliferator-activated receptor gamma, CCAAT-enhancer binding protein alpha, and leptin was suppressed by selenate. This pretreatment also upregulated selenoprotein S (SEPS1), an ER resident selenoprotein that reduces ER stress, and prevented dexamethasone-induced SEPS1 degradation during the early stage of adipogenesis. The selenate-inhibited adipogenesis was associated with an attenuation of ER stress. The expression of the ER stress marker genes was upregulated during the early stage of differentiation, whereas the selenate pretreatment suppressed the mRNA expression of the XBP1 and C/EBP homologous protein. The collective data suggest a preventive role of selenate and SEPS1 in adipogenesis, and support a novel dietary approach to prevent obesity.
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Affiliation(s)
- Choon Young Kim
- Department of Food and Nutrition, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk 38541, Korea.
| | - Kee-Hong Kim
- Department of Food Science, Purdue University, West Lafayette, IN 47897, USA.
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Tonoyama Y, Tsukada M, Imai Y, Sanada M, Aota S, Oka G, Sugiura S, Hori N, Kawachi H, Shimizu Y, Shimizu N. Establishment of a quantitative in vivo method for estimating adipose tissue volumes and the effects of dietary soy sauce oil on adipogenesis in medaka, Oryzias latipes. PLoS One 2018; 13:e0205888. [PMID: 30335858 PMCID: PMC6193695 DOI: 10.1371/journal.pone.0205888] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 10/03/2018] [Indexed: 11/25/2022] Open
Abstract
Adipose tissue, which is conserved in higher eukaryotes, plays central roles in controlling the body’s energy balance, including excess energy storage and energy expenditure during starvation. In adipogenesis, intranuclear receptor, peroxisome proliferator–activated receptor gamma (PPARγ) is a key molecule, and PPARγ agonists can promote adipogenesis. Many studies on the in vitro screening of PPARγ agonists with compounds derived from various materials have been reported; however, in vivo assays for quick examination of these feeding effects have not been established. In this study, we developed a technique using a lipophilic fluorescent reagent, Nile red to quantitatively estimate the adipose tissue volumes by using Japanese rice fish, medaka (Oryzias latipes) and studied effects of dietary soy sauce oil (SSO), which is a discarded by-product from Japanese traditional food and is known to have PPARγ-agonistic activity, on adipogenesis. We found that SSO feeding increased the adipose tissue volumes, and the expression levels of adipogenesis-related genes increased in these medaka larvae. These results suggest that SSO feeding increases the adipose tissue volumes through adipogenesis promotion by PPARγ-agonistic activity in medaka, and medaka is a powerful model for studying adipogenesis. Furthermore, our study also demonstrates the availability of SSO as a dietary additive for farmed fish.
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Affiliation(s)
- Yasuhiro Tonoyama
- Graduate School of Bioscience, Nagahama Institute for Bioscience and Technology, Nagahama, Shiga, Japan
- * E-mail: (YT); (HK)
| | - Masaki Tsukada
- Graduate School of Bioscience, Nagahama Institute for Bioscience and Technology, Nagahama, Shiga, Japan
| | - Yoshimasa Imai
- Graduate School of Bioscience, Nagahama Institute for Bioscience and Technology, Nagahama, Shiga, Japan
| | - Matoki Sanada
- Graduate School of Bioscience, Nagahama Institute for Bioscience and Technology, Nagahama, Shiga, Japan
| | - Syota Aota
- Graduate School of Bioscience, Nagahama Institute for Bioscience and Technology, Nagahama, Shiga, Japan
| | - Gouhei Oka
- Division of admission Center, Nagahama Institute for Bioscience and Technology, Nagahama, Shiga, Japan
| | - Shozo Sugiura
- School of Environmental Sciences, The University of Shiga Prefecture, Hikone, Shiga, Japan
| | - Nobuaki Hori
- Division of Research Management and External Cooperation, Nagahama Institute for Bioscience and Technology, Nagahama, Shiga, Japan
| | - Hiroyuki Kawachi
- Graduate School of Bioscience, Nagahama Institute for Bioscience and Technology, Nagahama, Shiga, Japan
- * E-mail: (YT); (HK)
| | - Yoshiko Shimizu
- Faculty of Health Sciences, Kyorin University, Mitaka, Tokyo, Japan
| | - Nobuyoshi Shimizu
- Graduate School of Bioscience, Nagahama Institute for Bioscience and Technology, Nagahama, Shiga, Japan
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Devchand PR, Liu T, Altman RB, FitzGerald GA, Schadt EE. The Pioglitazone Trek via Human PPAR Gamma: From Discovery to a Medicine at the FDA and Beyond. Front Pharmacol 2018; 9:1093. [PMID: 30337873 PMCID: PMC6180177 DOI: 10.3389/fphar.2018.01093] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 09/07/2018] [Indexed: 12/13/2022] Open
Abstract
For almost two decades, pioglitazone has been prescribed primarily to prevent and treat insulin resistance in some type 2 diabetic patients. In this review, we trace the path to discovery of pioglitazone as a thiazolidinedione compound, the glitazone tracks through the regulatory agencies, the trek to molecular agonism in the nucleus and the binding of pioglitazone to the nuclear receptor PPAR gamma. Given the rise in consumption of pioglitazone in T2D patients worldwide and the increased number of clinical trials currently testing alternate medical uses for this drug, there is also merit to some reflection on the reported adverse effects. Going forward, it is imperative to continue investigations into the mechanisms of actions of pioglitazone, the potential of glitazone drugs to contribute to unmet needs in complex diseases associated with the dynamics of adaptive homeostasis, and also the routes to minimizing adverse effects in every-day patients throughout the world.
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Affiliation(s)
- Pallavi R Devchand
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Tianyun Liu
- Department of Genetics, Stanford University, Stanford, CA, United States
| | - Russ B Altman
- Department of Genetics, Stanford University, Stanford, CA, United States.,Department of Bioengineering, Stanford University, Stanford, CA, United States
| | - Garret A FitzGerald
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Eric E Schadt
- SEMA4, a Mount Sinai Venture, Stamford, CT, United States.,Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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48
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Pesta M, Cedikova M, Dvorak P, Dvorakova J, Kulda V, Srbecka K, Muller L, Bouchalova V, Kralickova M, Babuska V, Kuncova J, Mullerova D. Trends in gene expression changes during adipogenesis in human adipose derived mesenchymal stem cells under dichlorodiphenyldichloroethylene exposure. Mol Cell Toxicol 2018. [DOI: 10.1007/s13273-018-0041-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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49
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Kraakman MJ, Liu Q, Postigo-Fernandez J, Ji R, Kon N, Larrea D, Namwanje M, Fan L, Chan M, Area-Gomez E, Fu W, Creusot RJ, Qiang L. PPARγ deacetylation dissociates thiazolidinedione's metabolic benefits from its adverse effects. J Clin Invest 2018; 128:2600-2612. [PMID: 29589839 DOI: 10.1172/jci98709] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 03/22/2018] [Indexed: 01/10/2023] Open
Abstract
Thiazolidinediones (TZDs) are PPARγ agonists with potent insulin-sensitizing effects. However, their use has been curtailed by substantial adverse effects on weight, bone, heart, and hemodynamic balance. TZDs induce the deacetylation of PPARγ on K268 and K293 to cause the browning of white adipocytes. Here, we show that targeted PPARγ mutations resulting in constitutive deacetylation (K268R/K293R, 2KR) increased energy expenditure and protected from visceral adiposity and diet-induced obesity by augmenting brown remodeling of white adipose tissues. Strikingly, when 2KR mice were treated with rosiglitazone, they maintained the insulin-sensitizing, glucose-lowering response to TZDs, while displaying little, if any, adverse effects on fat deposition, bone density, fluid retention, and cardiac hypertrophy. Thus, deacetylation appears to fulfill the goal of dissociating the metabolic benefits of PPARγ activation from its adverse effects. Strategies to leverage PPARγ deacetylation may lead to the design of safer, more effective agonists of this nuclear receptor in the treatment of metabolic diseases.
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Affiliation(s)
| | - Qiongming Liu
- Naomi Berrie Diabetes Center.,Department of Pathology and Cell Biology
| | - Jorge Postigo-Fernandez
- Naomi Berrie Diabetes Center.,Department of Medicine, Columbia Center for Translational Immunology
| | - Ruiping Ji
- Center for Advanced Cardiac Care, Department of Medicine, Division of Cardiology
| | - Ning Kon
- Institute for Cancer Genetics and Department of Pathology, and
| | - Delfina Larrea
- Department of Neurology, College of Physicians and Surgeons, Columbia University New York, New York, USA
| | - Maria Namwanje
- Naomi Berrie Diabetes Center.,Department of Pathology and Cell Biology
| | - Lihong Fan
- Naomi Berrie Diabetes Center.,Department of Pathology and Cell Biology.,Department of Cardiology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an City, Shaanxi Province, China
| | - Michelle Chan
- Department of Biological Sciences, Columbia University, New York, New York, USA
| | - Estela Area-Gomez
- Department of Neurology, College of Physicians and Surgeons, Columbia University New York, New York, USA
| | - Wenxian Fu
- Department of Pediatrics, UCSD, La Jolla, California, USA
| | - Remi J Creusot
- Naomi Berrie Diabetes Center.,Department of Medicine, Columbia Center for Translational Immunology
| | - Li Qiang
- Department of Pathology and Cell Biology
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50
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Briot A, Decaunes P, Volat F, Belles C, Coupaye M, Ledoux S, Bouloumié A. Senescence Alters PPARγ (Peroxisome Proliferator–Activated Receptor Gamma)-Dependent Fatty Acid Handling in Human Adipose Tissue Microvascular Endothelial Cells and Favors Inflammation. Arterioscler Thromb Vasc Biol 2018; 38:1134-1146. [DOI: 10.1161/atvbaha.118.310797] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 03/01/2018] [Indexed: 02/06/2023]
Abstract
Objective—
Adipose tissue (AT) dysfunction associated with obesity or aging is a major cause for lipid redistribution and the progression of cardiometabolic disorders. Our goal is to decipher the contribution of human AT microvascular endothelial cells (ECs) in the maintenance of fatty acid (FA) fluxes and the impact of senescence on their function.
Approach and Results—
We used freshly isolated primary microvascular ECs from human AT. Our data identified the endothelial FA handling machinery including FATPs (FA transport proteins) FATP1, FATP3, FATP4, and CD36 as well as FABP4 (FA binding protein 4). We showed that PPARγ (peroxisome proliferator–activated receptor gamma) regulates the expression of FATP1, CD36, and FABP4 and is a major regulator of FA uptake in human AT EC (hATEC). We provided evidence that endothelial PPARγ activity is modulated by senescence. Indeed, the positive regulation of FA transport by PPARγ agonist was abolished, whereas the emergence of an inflammatory response was favored in senescent hATEC. This was associated with the retention of nuclear FOXO1 (forkhead box protein O1), whereas nuclear PPARγ translocation was impaired.
Conclusions—
These data support the notion that PPARγ is a key regulator of primary hATEC function including FA handling and inflammatory response. However, the outcome of PPARγ activation is modulated by senescence, a phenomenon that may impact the ability of hATEC to properly respond to and handle lipid fluxes. Finally, our work highlights the role of hATEC in the regulation of FA fluxes and reveals that dysfunction of these cells with accelerated aging is likely to participate to AT dysfunction and the redistribution of lipids.
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Affiliation(s)
- Anaïs Briot
- From the Inserm, UMR1048, Team 1, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, Toulouse, Cedex 4, France (A. Briot, P.D., F.V., C.B., A. Bouloumié)
| | - Pauline Decaunes
- From the Inserm, UMR1048, Team 1, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, Toulouse, Cedex 4, France (A. Briot, P.D., F.V., C.B., A. Bouloumié)
| | - Fanny Volat
- From the Inserm, UMR1048, Team 1, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, Toulouse, Cedex 4, France (A. Briot, P.D., F.V., C.B., A. Bouloumié)
| | - Chloé Belles
- From the Inserm, UMR1048, Team 1, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, Toulouse, Cedex 4, France (A. Briot, P.D., F.V., C.B., A. Bouloumié)
| | - Muriel Coupaye
- Center Support of Obesity, Hôpital Louis Mourier (APHP), Colombes, and Faculté Paris Diderot, France (M.C., S.L.)
| | - Séverine Ledoux
- Center Support of Obesity, Hôpital Louis Mourier (APHP), Colombes, and Faculté Paris Diderot, France (M.C., S.L.)
| | - Anne Bouloumié
- From the Inserm, UMR1048, Team 1, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, Toulouse, Cedex 4, France (A. Briot, P.D., F.V., C.B., A. Bouloumié)
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