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1
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Ongaro L, Bernard DJ. Activin Actions in Adipocytes. J Clin Endocrinol Metab 2025; 110:1803-1810. [PMID: 40208114 DOI: 10.1210/clinem/dgaf233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/30/2025] [Accepted: 04/08/2025] [Indexed: 04/11/2025]
Abstract
Obesity is a growing global health problem characterized by excess fat accumulation. Though causes of obesity are multifactorial, glucagon-like peptide 1 receptor agonists have emerged as effective weight loss drugs. Nevertheless, these agents are expensive, not uniformly available, and must be used continuously. Moreover, side effects and low efficacy limit the use of these and related molecules in some individuals. Therefore, there is continued interest in characterizing mechanisms regulating adiposity to aid in the development of novel treatments. In recent years, there has been a growing appreciation for ligands of the TGFβ family, the activins, in adipocyte proliferation, differentiation, and function. Here, we review recent progress in understanding the role of these molecules, with a particular focus on the hepatokine, activin E, in lipolysis and diet-induced obesity.
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Affiliation(s)
- Luisina Ongaro
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada
| | - Daniel Jay Bernard
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada
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2
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Huang K, Chiang Y, Ali M, Hsia S. Cisplatin-Induced Muscle Wasting and Atrophy: Molecular Mechanism and Potential Therapeutic Interventions. J Cachexia Sarcopenia Muscle 2025; 16:e13817. [PMID: 40343378 PMCID: PMC12059472 DOI: 10.1002/jcsm.13817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 05/11/2025] Open
Abstract
Platinum-based chemotherapeutics, particularly cisplatin, are crucial in the treatment of various malignancies due to their strong antitumor effects. However, a significant side effect of cisplatin is muscle atrophy, which severely impairs physical strength, diminishes quality of life and complicates cancer therapy. Cisplatin-induced muscle wasting arises from a complex interplay of enhanced proteolysis, reduced muscle protein synthesis and systemic inflammation. Understanding the underlying molecular mechanisms of muscle atrophy is vital for identifying new therapeutic targets. This review systematically explores molecular-based therapies and plant-derived natural compounds, providing a comprehensive overview of their efficacy in vivo and in vitro for preventing cisplatin-induced muscle atrophy. Both molecular-based therapies and plant-derived natural compounds present promising strategies for mitigating cisplatin-induced muscle atrophy. Ghrelin, growth hormone secretagogues and testosterone stimulate anabolic pathways and reduce muscle degradation, whereas natural compounds like capsaicin and naringenin exert protective effects by reducing inflammation and oxidative stress. A better understanding of the pathophysiology of muscle atrophy, combined with optimized therapeutic applications, may facilitate the clinical translation of these interventions to improve outcomes for cancer patients undergoing chemotherapy.
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Affiliation(s)
- Ko‐Chieh Huang
- School of Nutrition and Health Sciences, College of NutritionTaipei Medical UniversityTaipeiTaiwan
| | - Yi‐Fen Chiang
- School of Nutrition and Health Sciences, College of NutritionTaipei Medical UniversityTaipeiTaiwan
| | - Mohamed Ali
- Clinical Pharmacy Department, Faculty of PharmacyAin Shams UniversityCairoEgypt
- Department of Obstetrics and GynecologyUniversity of ChicagoChicagoIllinoisUSA
| | - Shih‐Min Hsia
- School of Nutrition and Health Sciences, College of NutritionTaipei Medical UniversityTaipeiTaiwan
- Graduate Institute of Metabolism and Obesity Sciences, College of NutritionTaipei Medical UniversityTaipeiTaiwan
- School of Food and SafetyTaipei Medical UniversityTaipeiTaiwan
- Nutrition Research CenterTaipei Medical University HospitalTaipeiTaiwan
- TMU Research Center for Digestive MedicineTaipei Medical UniversityTaipeiTaiwan
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John S, Bhowmick K, Park A, Huang H, Yang X, Mishra L. Recent advances in targeting obesity, with a focus on TGF-β signaling and vagus nerve innervation. Bioelectron Med 2025; 11:10. [PMID: 40301996 PMCID: PMC12042417 DOI: 10.1186/s42234-025-00172-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/31/2025] [Indexed: 05/01/2025] Open
Abstract
Over a third of the global population is affected by obesity, fatty liver disease (Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD), and its severe form, MASH (Metabolic Dysfunction-Associated Steatohepatitis), which can ultimately progress to hepatocellular carcinoma (HCC). Recent advancements include therapeutics such as glucagon-like peptide 1 (GLP-1) agonists and neural/vagal modulation strategies for these disorders. Among the many pathways regulating these conditions, emerging insights into transforming growth factor-β (TGF-β) signaling highlight potential future targets through its role in pathophysiological processes such as adipogenesis, inflammation, and fibrosis. Vagus nerve innervation in the gastrointestinal tract is involved in satiety regulation and energy homeostasis, and vagus nerve stimulation has been applied in weight loss and diabetes. This review explores clinical trials in obesity, novel therapeutic targets, and the role of TGF-β signaling and vagus nerve modulation in obesity-related liver diseases and HCC.
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Affiliation(s)
- Sahara John
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Krishanu Bhowmick
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA
| | - Andrew Park
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Hai Huang
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Xiaochun Yang
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
| | - Lopa Mishra
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
- Department of Surgery, George Washington University, Washington, DC, 20037, USA.
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Bretscher H, O’Connor MB. Glycogen homeostasis and mitochondrial DNA expression require motor neuron to muscle TGF-β/Activin signaling in Drosophila. iScience 2025; 28:111611. [PMID: 39850360 PMCID: PMC11754121 DOI: 10.1016/j.isci.2024.111611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 10/30/2024] [Accepted: 12/12/2024] [Indexed: 01/25/2025] Open
Abstract
Maintaining metabolic homeostasis requires coordinated nutrient utilization between intracellular organelles and across multiple organ systems. Many organs rely heavily on mitochondria to generate (ATP) from glucose, or stored glycogen. Proteins required for ATP generation are encoded in both nuclear and mitochondrial DNA (mtDNA). We show that motoneuron to muscle signaling by the TGFβ/Activin family member Actβ positively regulates glycogen levels during Drosophila development. Remarkably, we find that levels of stored glycogen are unaffected by altering cytoplasmic glucose catabolism. Instead, loss of Actβ reduces levels of nuclearly encoded genes required for mtDNA replication, transcription, and translation and mtDNA levels. Direct RNAi knockdown of nuclearly encoded mtDNA expression factors in muscle also results in decreased glycogen stores. Lastly, expressing an activated form of the type I receptor Baboon in muscle restores both glycogen and mtDNA levels in actβ mutants, thereby confirming a direct link between Actβ signaling, glycogen homeostasis, and mtDNA expression factors.
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Affiliation(s)
- Heidi Bretscher
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
| | - Michael B. O’Connor
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
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Kaur M, Misra S. Bimagrumab: an investigational human monoclonal antibody against activin type II receptors for treating obesity. J Basic Clin Physiol Pharmacol 2024; 35:325-334. [PMID: 39385353 DOI: 10.1515/jbcpp-2024-0065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024]
Abstract
Bimagrumab is a human monoclonal antibody that prevents activin type II receptors (ActRII) from functioning. This antibody has a higher affinity for muscle activin-2 receptors than natural ligands such as activin and myostatin, which act as negative muscle growth regulators. Blocking the activin receptor with bimagrumab could be a new pharmaceutical approach for managing patients with obesity and type 2 diabetes mellitus (T2DM). Bimagrumab has anabolic effects on skeletal muscle mass by preventing myostatin binding and other negative muscle growth regulators. Preclinical animal models have also shown that ActRII blockade promotes actions beyond skeletal muscle, including effects on brown adipose tissue (BAT) differentiation and activity. In a phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of total body fat mass (FM), lean mass (LM) gain, and metabolic improvements over 48 weeks in overweight or obese patients with type 2 diabetes. The trial involved [number of participants], and the results showed [specific findings]. Currently, Bimagrumab is being evaluated for its potential to treat muscle wasting, functional loss in hip fractures and sarcopenia, as well as obesity. However, it is essential to note that Bimagrumab also blocks the effects of other ActRII ligands, which play a role in the neurohormonal axes, pituitary, gonads, and adrenal glands. These observations suggest that bimagrumab might represent a new approach for treating patients with obesity and related metabolic disturbances.
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MESH Headings
- Humans
- Activin Receptors, Type II/antagonists & inhibitors
- Obesity/drug therapy
- Animals
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Diabetes Mellitus, Type 2/drug therapy
- Muscle, Skeletal/drug effects
- Muscle, Skeletal/metabolism
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
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Affiliation(s)
- Manmeet Kaur
- Department of Pharmacology, Kalpana Chawla Government Medical College, Karnal, India
| | - Saurav Misra
- Department of Pharmacology, Kalpana Chawla Government Medical College, Karnal, India
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Zhang Z, Chang L, Wang B, Wei Y, Li X, Li X, Zhang Y, Wang K, Qiao R, Yang F, Yu T, Han X. Differential chromatin accessibility and Gene Expression Associated with Backfat Deposition in pigs. BMC Genomics 2024; 25:902. [PMID: 39349998 PMCID: PMC11441165 DOI: 10.1186/s12864-024-10805-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/17/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Backfat serves as a vital fat reservoir in pigs, and its excessive accumulation will adversely impact pig growth performance, farming efficiency, and pork quality. The aim of this research is to integrate assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing (RNA-seq) to explore the molecular mechanisms underlying porcine backfat deposition. RESULTS ATAC-seq analysis identified 568 genes originating from 698 regions exhibiting differential accessibility, which were significantly enriched in pathways pertinent to adipocyte differentiation and lipid metabolism. Besides, a total of 283 transcription factors (TFs) were identified by motif analysis. RNA-seq analysis revealed 978 differentially expressed genes (DEGs), which were enriched in pathways related to energy metabolism, cell cycle and signal transduction. The integration of ATAC-seq and RNA-seq data indicates that DEG expression levels are associated with chromatin accessibility. This comprehensive study highlights the involvement of critical pathways, including the Wnt signaling pathway, Jak-STAT signaling pathway, and fatty acid degradation, in the regulation of backfat deposition. Through rigorous analysis, we identified several candidate genes (LEP, CTBP2, EHHADH, OSMR, TCF7L2, BCL2, FGF1, UCP2, CCND1, TIMP1, and VDR) as potentially significant contributors to backfat deposition. Additionally, we constructed TF-TF and TF-target gene regulatory networks and identified a series of potential TFs related to backfat deposition (FOS, STAT3, SMAD3, and ESR1). CONCLUSIONS This study represents the first application of ATAC-seq and RNA-seq, affording a novel perspective into the mechanisms underlying backfat deposition and providing invaluable resources for the enhancement of pig breeding programs.
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Affiliation(s)
- Zhe Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China
| | - Lebin Chang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China
| | - Bingjie Wang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China
| | - Yilin Wei
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China
| | - Xinjian Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China
- Sanya Institute, Hainan Academy of Agricultural Science, Sanya, 572025, China
| | - Xiuling Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China
| | - Yongqian Zhang
- Henan Yifa Animal Husbandry Co., Ltd, Hebi, 458000, China
| | - Kejun Wang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China
| | - Ruimin Qiao
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China
| | - Feng Yang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China
| | - Tong Yu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China
| | - Xuelei Han
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046, China.
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7
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Bretscher H, O’Connor MB. Glycogen homeostasis and mtDNA expression require motor neuron to muscle TGFβ/Activin Signaling in Drosophila. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.25.600699. [PMID: 39131342 PMCID: PMC11312462 DOI: 10.1101/2024.06.25.600699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Maintaining metabolic homeostasis requires coordinated nutrient utilization between intracellular organelles and across multiple organ systems. Many organs rely heavily on mitochondria to generate (ATP) from glucose, or stored glycogen. Proteins required for ATP generation are encoded in both nuclear and mitochondrial DNA (mtDNA). We show that motoneuron to muscle signaling by the TGFβ/Activin family member Actβ positively regulates glycogen levels during Drosophila development. Remarkably, we find that levels of stored glycogen are unaffected by altering cytoplasmic glucose catabolism. Instead, Actβ loss reduces levels of mtDNA and nuclearly encoded genes required for mtDNA replication, transcription and translation. Direct RNAi mediated knockdown of these same nuclearly encoded mtDNA expression factors also results in decreased glycogen stores. Lastly, we find that expressing an activated form of the type I receptor Baboon in muscle restores both glycogen and mtDNA levels in actβ mutants, thereby confirming a direct link between Actβ signaling, glycogen homeostasis and mtDNA expression.
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Affiliation(s)
- Heidi Bretscher
- Department of Genetics, Cell Biology and Development University of Minnesota, Minneapolis, MN 55455
| | - Michael B. O’Connor
- Department of Genetics, Cell Biology and Development University of Minnesota, Minneapolis, MN 55455
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8
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Dole NS, Betancourt-Torres A, Kaya S, Obata Y, Schurman CA, Yoon J, Yee CS, Khanal V, Luna CA, Carroll M, Salinas JJ, Miclau E, Acevedo C, Alliston T. High-fat and high-carbohydrate diets increase bone fragility through TGF-β-dependent control of osteocyte function. JCI Insight 2024; 9:e175103. [PMID: 39171528 PMCID: PMC11343608 DOI: 10.1172/jci.insight.175103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 07/03/2024] [Indexed: 08/23/2024] Open
Abstract
Obesity can increase the risk of bone fragility, even when bone mass is intact. This fragility stems from poor bone quality, potentially caused by deficiencies in bone matrix material properties. However, cellular and molecular mechanisms leading to obesity-related bone fragility are not fully understood. Using male mouse models of obesity, we discovered TGF-β signaling plays a critical role in mediating the effects of obesity on bone. High-carbohydrate and high-fat diets increase TGF-β signaling in osteocytes, which impairs their mitochondrial function, increases cellular senescence, and compromises perilacunar/canalicular remodeling and bone quality. By specifically inhibiting TGF-β signaling in mouse osteocytes, some of the negative effects of high-fat and high-carbohydrate diets on bones, including the lacunocanalicular network, perilacunar/canalicular remodeling, senescence, and mechanical properties such as yield stress, were mitigated. DMP1-Cre-mediated deletion of TGF-β receptor II also blunted adverse effects of high-fat and high-carbohydrate diets on energy balance and metabolism. These findings suggest osteocytes are key in controlling bone quality in response to high-fat and high-carbohydrate diets. Calibrating osteocyte function could mitigate bone fragility associated with metabolic diseases while reestablishing energy balance.
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Affiliation(s)
- Neha S. Dole
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock Arkansas, USA
| | - Andrés Betancourt-Torres
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Serra Kaya
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Yoshihiro Obata
- Department of Mechanical Engineering, University of Utah, Salt Lake City, Utah, USA
| | - Charles A. Schurman
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
- UC Berkeley/UCSF Graduate Program in Bioengineering, San Francisco, California, USA
| | - Jihee Yoon
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Cristal S. Yee
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Vivek Khanal
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock Arkansas, USA
| | - Clarissa Aguirre Luna
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Madeline Carroll
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock Arkansas, USA
| | - Jennifer J. Salinas
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Elizabeth Miclau
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Claire Acevedo
- Department of Mechanical Engineering, University of Utah, Salt Lake City, Utah, USA
- Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah, USA
- Department of Mechanical and Aerospace Engineering, University of California, San Diego, San Diego, California, USA
| | - Tamara Alliston
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
- UC Berkeley/UCSF Graduate Program in Bioengineering, San Francisco, California, USA
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9
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Fang Y, Feng H, Zhang B, Zhang S, Zhou Y, Hao P, Zhou Z, Zhou S, Li N, Hui Y, Ma L, Xiong J, Wu J, Liu L, Zhang X. Cytosolic pH is a direct nexus in linking environmental cues with insulin processing and secretion in pancreatic β cells. Cell Metab 2024; 36:1237-1251.e4. [PMID: 38513648 DOI: 10.1016/j.cmet.2024.02.012] [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: 04/12/2023] [Revised: 09/01/2023] [Accepted: 02/22/2024] [Indexed: 03/23/2024]
Abstract
Pancreatic β cells actively respond to glucose fluctuations through regulating insulin processing and secretion. However, how this process is elaborately tuned in circumstance of variable microenvironments as well as β cell-intrinsic states and whether its dysfunction links to metabolic diseases remain largely elusive. Here, we show that the cytosolic pH (pHc) in β cells is increased upon glucose challenge, which can be sensed by Smad5 via its nucleocytoplasmic shuttling. Lesion of Smad5 in β cells results in hyperglycemia and glucose intolerance due to insulin processing and secretion deficiency. The role of Smad5 in regulating insulin processing and secretion attributes to its non-canonical function by regulating V-ATPase activity for granule acidification. Genetic mutation of Smad5 or administration of alkaline water to mirror cytosolic alkalization ameliorated glucose intolerance in high-fat diet (HFD)-treated mice. Collectively, our findings suggest that pHc is a direct nexus in linking environmental cues with insulin processing and secretion in β cells.
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Affiliation(s)
- Yujiang Fang
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China.
| | - Hexi Feng
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Bowen Zhang
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Shuwei Zhang
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Yanjie Zhou
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Pengcheng Hao
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Zhongshu Zhou
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Shanshan Zhou
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Nan Li
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Yi Hui
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Lin Ma
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Jie Xiong
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Jinjin Wu
- Shanghai Children's Medical Center, Shanghai Jiaotong University, Shanghai, China
| | - Ling Liu
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China.
| | - Xiaoqing Zhang
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China; Key Laboratory of Neuroregeneration of Shanghai Universities, School of Medicine, Tongji University, Shanghai, China; Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, China.
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10
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Huang J, Ye J, Gao Y, Wang Y, Zhao Q, Lou T, Lai W. Identification of proteins related to SIS3 by iTRAQ and PRM-based comparative proteomic analysis in cisplatin-induced acute kidney injury. PeerJ 2024; 12:e17485. [PMID: 38854800 PMCID: PMC11160430 DOI: 10.7717/peerj.17485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/08/2024] [Indexed: 06/11/2024] Open
Abstract
Background Cisplatin is a commonly used nephrotoxic drug and can cause acute kidney injury (AKI). In the present study, isobaric tags for relative and absolute quantification (iTRAQ) and parallel reaction monitoring (PRM)-based comparative proteomics were used to analyze differentially expressed proteins (DEPs) to determine the key molecular mechanism in mice with cisplatin-induced AKI in the presence or absence of SIS3, a specific p-smad3 inhibitor, intervention. Methods The cisplatin-induced AKI mouse model was established and treated with SIS3. We used iTRAQ to search for DEPs, PRM to verify key DEPs and combined Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for bioinformatics analysis. We then assessed lipid deposition, malondialdehyde (MDA) and reactive oxygen species (ROS) and detected the expression of SREBF1, SCD1, CPT1A, PPARα and NDRG1 in vitro. Results Proteomic analysis showed that the identified DEPs were mainly enriched in energy metabolism pathways, especially in lipid metabolism. When SIS3 was applied to inhibit the phosphorylation of Smad3, the expression of NDRG1 and fatty acid oxidation key proteins CPT1A and PPARα increased, the expression of lipid synthesis related proteins SREBF1 and SCD1 decreased and the production of lipid droplets, MDA and ROS decreased. Conclusion SIS3 alleviates oxidative stress, reduces lipid accumulation and promotes fatty acid oxidation through NDRG1 in cisplatin-induced AKI. Our study provides a new candidate protein for elucidating the molecular mechanisms of fatty acid metabolism disorders in cisplatin-induced acute kidney injury.
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Affiliation(s)
- Jiayan Huang
- Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jian Ye
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yi Gao
- Department of Critical Care Medicine/ICU (Intensive Care Unit), The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yu Wang
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Qing Zhao
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Tanqi Lou
- Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Weiyan Lai
- Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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11
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Saxena G, Gallagher S, Law TD, Maschari D, Walsh E, Dudley C, Brault JJ, Consitt LA. Sex-specific increases in myostatin and SMAD3 contribute to obesity-related insulin resistance in human skeletal muscle and primary human myotubes. Am J Physiol Endocrinol Metab 2024; 326:E352-E365. [PMID: 38088865 PMCID: PMC11193514 DOI: 10.1152/ajpendo.00199.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 01/16/2024]
Abstract
The purpose of the present study was to determine the effects of obesity and biological sex on myostatin expression in humans and to examine the direct effects of myostatin, SMAD2, and SMAD3 on insulin signaling in primary human skeletal muscle cells (HSkMCs). For cohort 1, 15 lean [body mass index (BMI): 22.1 ± 0.5 kg/m2; n = 8 males; n = 7 females] and 14 obese (BMI: 40.6 ± 1.4 kg/m2; n = 7 males; n = 7 females) individuals underwent skeletal muscle biopsies and an oral glucose tolerance test. For cohort 2, 14 young lean (BMI: 22.4 ± 1.9 kg/m2; n = 6 males; n = 8 females) and 14 obese (BMI: 39.3 ± 7.9 kg/m2; n = 6 males; n = 8 females) individuals underwent muscle biopsies for primary HSkMC experiments. Plasma mature myostatin (P = 0.041), skeletal muscle precursor myostatin (P = 0.048), and skeletal muscle SMAD3 (P = 0.029) were elevated in obese females compared to lean females, and plasma mature myostatin (r = 0.58, P = 0.029) and skeletal muscle SMAD3 (r = 0.56, P = 0.037) were associated with insulin resistance in females but not males. Twenty-four hours of myostatin treatment impaired insulin signaling in primary HSkMCs derived from females (P < 0.024) but not males. Overexpression of SMAD3, but not SMAD2, impaired insulin-stimulated AS160 phosphorylation in HSkMCs derived from lean females (-27%, P = 0.040), whereas silencing SMAD3 improved insulin-stimulated AS160 phosphorylation and insulin-stimulated glucose uptake (25%, P < 0.014) in HSkMCs derived from obese females. These results suggest for the first time that myostatin-induced impairments in skeletal muscle insulin signaling are sex specific and that increased body fat in females is associated with detrimental elevations in myostatin and SMAD3, which contribute to obesity-related insulin resistance.NEW & NOTEWORTHY Obesity is considered a main risk factor for the development of insulin resistance and type 2 diabetes. The present study utilizes in vivo and in vitro experiments in human skeletal muscle to demonstrate for the first time that females are inherently more susceptible to myostatin-induced insulin resistance, which is further enhanced with obesity due to increased myostatin and SMAD3 expression.
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Affiliation(s)
- Gunjan Saxena
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, United States
| | - Sean Gallagher
- Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, United States
| | - Timothy D Law
- Ohio Musculoskeletal and Neurological Institute, Ohio University, Athens, Ohio, United States
| | - Dominic Maschari
- College of Health Sciences and Professions, Ohio University, Athens, Ohio, United States
| | - Erin Walsh
- Biological Sciences Department, Ohio University, Athens, Ohio, United States
| | - Courtney Dudley
- Biological Sciences Department, Ohio University, Athens, Ohio, United States
| | - Jeffrey J Brault
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Indiana Center for Musculoskeletal Health, Indianapolis, Indiana, United States
| | - Leslie A Consitt
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, United States
- Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, United States
- Ohio Musculoskeletal and Neurological Institute, Ohio University, Athens, Ohio, United States
- Diabetes Institute, Ohio University, Athens, Ohio, United States
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12
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Pan Q, Ai W, Guo S. TGF-β1 Signaling Impairs Metformin Action on Glycemic Control. Int J Mol Sci 2024; 25:2424. [PMID: 38397103 PMCID: PMC10889280 DOI: 10.3390/ijms25042424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 02/02/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Hyperglycemia is a hallmark of type 2 diabetes (T2D). Metformin, the first-line drug used to treat T2D, maintains blood glucose within a normal range by suppressing hepatic glucose production (HGP). However, resistance to metformin treatment is developed in most T2D patients over time. Transforming growth factor beta 1 (TGF-β1) levels are elevated both in the liver and serum of T2D humans and mice. Here, we found that TGF-β1 treatment impairs metformin action on suppressing HGP via inhibiting AMPK phosphorylation at Threonine 172 (T172). Hepatic TGF-β1 deficiency improves metformin action on glycemic control in high fat diet (HFD)-induced obese mice. In our hepatic insulin resistant mouse model (hepatic insulin receptor substrate 1 (IRS1) and IRS2 double knockout (DKO)), metformin action on glycemic control was impaired, which is largely improved by further deletion of hepatic TGF-β1 (TKObeta1) or hepatic Foxo1 (TKOfoxo1). Moreover, blockade of TGF-β1 signaling by chemical inhibitor of TGF-β1 type I receptor LY2157299 improves to metformin sensitivity in mice. Taken together, our current study suggests that hepatic TGF-β1 signaling impairs metformin action on glycemic control, and suppression of TGF-β1 signaling could serve as part of combination therapy with metformin for T2D treatment.
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Affiliation(s)
| | | | - Shaodong Guo
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX 77843, USA; (Q.P.); (W.A.)
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13
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Engin AB, Engin A. MicroRNAs as Epigenetic Regulators of Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:595-627. [PMID: 39287866 DOI: 10.1007/978-3-031-63657-8_20] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective micro-ribonucleic acids (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block the expression of master regulators of adipogenesis. Since the specific miRNAs display different expressions during adipogenesis, in mature adipocytes and permanent obesity, their use as biomarkers or therapeutic targets is feasible. Upregulated miRNAs in persistent obesity are downregulated during adipogenesis. Moreover, some of the downregulated miRNAs in obese individuals are upregulated in mature adipocytes. Induction of adipocyte stress and hypertrophy leads to the release of adipocyte-derived exosomes (AdEXs) that contain the cargo molecules, miRNAs. miRNAs are important messengers for intercellular communication involved in metabolic responses and have very specific signatures that direct the metabolic activity of target cells. While each miRNA targets multiple messenger RNAs (mRNAs), which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. Deletion of the miRNA-processing enzyme DICER in pro-opiomelanocortin-expressing cells results in obesity, which is characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism, and alterations in the pituitary-adrenal axis. In recent years, RNA-based therapeutical approaches have entered clinical trials as novel therapies against overweight and its complications. Development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor-associated factor 6 activity, lipolysis, lipotoxicity, and insulin resistance are effectively controlled by miRNAs. Thereby, miRNAs as epigenetic regulators are used to determine the new gene transcripts and therapeutic targets.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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14
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Hua Y, Xie D, Zhang Y, Wang M, Wen W, Sun J. Identification and analysis of key genes in adipose tissue for human obesity based on bioinformatics. Gene 2023; 888:147755. [PMID: 37659596 DOI: 10.1016/j.gene.2023.147755] [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: 07/09/2023] [Revised: 08/17/2023] [Accepted: 08/30/2023] [Indexed: 09/04/2023]
Abstract
BACKGROUND Obesity is a complex condition that is affected by a variety of factors, including the environment, behavior, and genetics. However, the genetic mechanisms underlying obesity remains poorly elucidated. Therefore, our study aimed at identifying key genes for human obesity using bioinformatics analysis. METHODS The microarray datasets of adipose tissue in humans were downloaded from the Gene Expression Omnibus (GEO) database. After the selection of differentially expressed genes (DEGs), we used Lasso regression and Support Vector Machine (SVM) algorithm to further identify the feature genes. Moreover, immune cell infiltration analysis, gene set variation analysis (GSVA), GeneCards database and transcriptional regulation analysis were conducted to study the potential mechanisms by which the feature genes may impact obesity. We utilized receiver operating characteristic (ROC) curve to analysis the diagnostic efficacy of feature genes. Finally, we verified the feature genes in cell experiments and animal experiments. The statistical analyses in validation experiments were conducted using SPSS version 28.0, and the graph were generated using GraphPad Prism 9.0 software. The bioinformatics analyses were conducted using R language (version 4.2.2), with a significance threshold of p < 0.05 used. RESULTS 199 DEGs were selected using Limma package, and subsequently, 5 feature genes (EGR2, NPY1R, GREM1, BMP3 and COL8A1) were selected through Lasso regression and SVM algorithm. Through various bioinformatics analyses, we found some signaling pathways by which feature genes influence obesity and also revealed the crucial role of these genes in the immune microenvironment, as well as their strong correlations with obesity-related genes. Additionally, ROC curve showed that all the feature genes had good predictive and diagnostic efficiency in obesity. Finally, after validation through in vitro experiments, EGR2, NPY1R and GREM1 were identified as the key genes. CONCLUSIONS This study identified EGR2, GREM1 and NPY1R as the potential key genes and potential diagnostic biomarkers for obesity in humans. Moreover, EGR2 was discovered as a key gene for obesity in human adipose tissue for the first time, which may provide novel targets for diagnosing and treating obesity.
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Affiliation(s)
- Yuchen Hua
- The Second School of Clinical Medicine, Southern Medical University, No.1023, South Shatai Road, Baiyun District, Guangzhou, Guangdong 510515, China
| | - Danyingzhu Xie
- Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong Province 510282, China
| | - Yugang Zhang
- Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong Province 510282, China
| | - Ming Wang
- Department of Traditional Chinese Medicine, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong Province 510282, China.
| | - Weiheng Wen
- Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong Province 510282, China.
| | - Jia Sun
- Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong Province 510282, China.
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Qahaz N, Lone IM, Khadija A, Ghnaim A, Zohud O, Nun NB, Nashef A, Abu El-Naaj I, Iraqi FA. Host Genetic Background Effect on Body Weight Changes Influenced by Heterozygous Smad4 Knockout Using Collaborative Cross Mouse Population. Int J Mol Sci 2023; 24:16136. [PMID: 38003328 PMCID: PMC10671513 DOI: 10.3390/ijms242216136] [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: 09/22/2023] [Revised: 10/29/2023] [Accepted: 10/31/2023] [Indexed: 11/26/2023] Open
Abstract
Obesity and its attendant conditions have become major health problems worldwide, and obesity is currently ranked as the fifth most common cause of death globally. Complex environmental and genetic factors are causes of the current obesity epidemic. Diet, lifestyle, chemical exposure, and other confounding factors are difficult to manage in humans. The mice model is helpful in researching genetic BW gain because genetic and environmental risk factors can be controlled in mice. Studies in mouse strains with various genetic backgrounds and established genetic structures provide unparalleled opportunities to find and analyze trait-related genomic loci. In this study, we used the Collaborative Cross (CC), a large panel of recombinant inbred mouse strains, to present a predictive study using heterozygous Smad4 knockout profiles of CC mice to understand and effectively identify predispositions to body weight gain. Male C57Bl/6J Smad4+/- mice were mated with female mice from 10 different CC lines to create F1 mice (Smad4+/-x CC). Body weight (BW) was measured weekly until week 16 and then monthly until the end of the study (week 48). The heritability (H2) of the assessed traits was estimated and presented. Comparative analysis of various machine learning algorithms for predicting the BW changes and genotype of mice was conducted. Our data showed that the body weight records of F1 mice with different CC lines differed between wild-type and mutant Smad4 mice during the experiment. Genetic background affects weight gain and some lines gained more weight in the presence of heterozygous Smad4 knockout, while others gained less, but, in general, the mutation caused overweight mice, except for a few lines. In both control and mutant groups, female %BW had a higher heritability (H2) value than males. Additionally, both sexes with wild-type genotypes showed higher heritability values than the mutant group. Logistic regression provides the most accurate mouse genotype predictions using machine learning. We plan to validate the proposed method on more CC lines and mice per line to expand the literature on machine learning for BW prediction.
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Affiliation(s)
- Nayrouz Qahaz
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel; (N.Q.); (I.M.L.); (A.K.); (A.G.); (O.Z.); (N.B.N.)
| | - Iqbal M. Lone
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel; (N.Q.); (I.M.L.); (A.K.); (A.G.); (O.Z.); (N.B.N.)
| | - Aya Khadija
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel; (N.Q.); (I.M.L.); (A.K.); (A.G.); (O.Z.); (N.B.N.)
| | - Aya Ghnaim
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel; (N.Q.); (I.M.L.); (A.K.); (A.G.); (O.Z.); (N.B.N.)
| | - Osayd Zohud
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel; (N.Q.); (I.M.L.); (A.K.); (A.G.); (O.Z.); (N.B.N.)
| | - Nadav Ben Nun
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel; (N.Q.); (I.M.L.); (A.K.); (A.G.); (O.Z.); (N.B.N.)
| | - Aysar Nashef
- Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Poriya 15208, Israel; (A.N.); (I.A.E.-N.)
| | - Imad Abu El-Naaj
- Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Poriya 15208, Israel; (A.N.); (I.A.E.-N.)
| | - Fuad A. Iraqi
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel; (N.Q.); (I.M.L.); (A.K.); (A.G.); (O.Z.); (N.B.N.)
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16
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Chen Y, Pan Q, Liao W, Ai W, Yang S, Guo S. Transcription Factor Forkhead Box O1 Mediates Transforming Growth Factor-β1-Induced Apoptosis in Hepatocytes. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1143-1155. [PMID: 37263346 PMCID: PMC10477955 DOI: 10.1016/j.ajpath.2023.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/27/2023] [Accepted: 05/18/2023] [Indexed: 06/03/2023]
Abstract
Dysregulation of hepatocyte apoptosis is associated with several types of chronic liver diseases. Transforming growth factor-β1 (TGF-β1) is a well-known pro-apoptotic factor in the liver, which constitutes a receptor complex composed of TGF-β receptor I and II, along with transcription factor Smad proteins. As a member of the forkhead box O (Foxo) class of transcription factors, Foxo1 is a predominant regulator of hepatic glucose production and apoptosis. This study investigated the potential relationship between TGF-β1 signaling and Foxo1 in control of apoptosis in hepatocytes. TGF-β1 induced hepatocyte apoptosis in a Foxo1-dependent manner in hepatocytes isolated from both wild-type and liver-specific Foxo1 knockout mice. TGF-β1 activated protein kinase A through TGF-β receptor I-Smad3, followed by phosphorylation of Foxo1 at Ser273 in promotion of apoptosis in hepatocytes. Moreover, Smad3 overexpression in the liver of mice promoted the levels of phosphorylated Foxo1-S273, total Foxo1, and a Foxo1-target pro-apoptotic gene Bim, which eventually resulted in hepatocyte apoptosis. The study further demonstrated a crucial role of Foxo1-S273 phosphorylation in the pro-apoptotic effect of TGF-β1 by using hepatocytes isolated from Foxo1-S273A/A knock-in mice, in which the phosphorylation of Foxo1-S273 was disrupted. Taken together, this study established a novel role of TGF-β1→protein kinase A→Foxo1 signaling cascades in control of hepatocyte survival.
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Affiliation(s)
- Yunmei Chen
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Quan Pan
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Wang Liao
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Weiqi Ai
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Sijun Yang
- Institute of Animal Model for Human Disease, Wuhan University, Wuhan, China
| | - Shaodong Guo
- Department of Nutrition, Texas A&M University, College Station, Texas.
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Pan Q, Ai W, Chen Y, Kim DM, Shen Z, Yang W, Jiang W, Sun Y, Safe S, Guo S. Reciprocal Regulation of Hepatic TGF-β1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure. Diabetes 2023; 72:1193-1206. [PMID: 37343276 PMCID: PMC10450826 DOI: 10.2337/db23-0180] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 06/13/2023] [Indexed: 06/23/2023]
Abstract
UNLABELLED Obesity and insulin resistance are risk factors for the pathogenesis of type 2 diabetes (T2D). Here, we report that hepatic TGF-β1 expression positively correlates with obesity and insulin resistance in mice and humans. Hepatic TGF-β1 deficiency decreased blood glucose levels in lean mice and improved glucose and energy dysregulations in diet-induced obese (DIO) mice and diabetic mice. Conversely, overexpression of TGF-β1 in the liver exacerbated metabolic dysfunctions in DIO mice. Mechanistically, hepatic TGF-β1 and Foxo1 are reciprocally regulated: fasting or insulin resistance caused Foxo1 activation, increasing TGF-β1 expression, which, in turn, activated protein kinase A, stimulating Foxo1-S273 phosphorylation to promote Foxo1-mediated gluconeogenesis. Disruption of TGF-β1→Foxo1→TGF-β1 looping by deleting TGF-β1 receptor II in the liver or by blocking Foxo1-S273 phosphorylation ameliorated hyperglycemia and improved energy metabolism in adipose tissues. Taken together, our studies reveal that hepatic TGF-β1→Foxo1→TGF-β1 looping could be a potential therapeutic target for prevention and treatment of obesity and T2D. ARTICLE HIGHLIGHTS Hepatic TGF-β1 levels are increased in obese humans and mice. Hepatic TGF-β1 maintains glucose homeostasis in lean mice and causes glucose and energy dysregulations in obese and diabetic mice. Hepatic TGF-β1 exerts an autocrine effect to promote hepatic gluconeogenesis via cAMP-dependent protein kinase-mediated Foxo1 phosphorylation at serine 273, endocrine effects on brown adipose tissue action, and inguinal white adipose tissue browning (beige fat), causing energy imbalance in obese and insulin-resistant mice. TGF-β1→Foxo1→TGF-β1 looping in hepatocytes plays a critical role in controlling glucose and energy metabolism in health and disease.
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Affiliation(s)
- Quan Pan
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Weiqi Ai
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Yunmei Chen
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Da Mi Kim
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Zheng Shen
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Wanbao Yang
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Wen Jiang
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Yuxiang Sun
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX
| | - Shaodong Guo
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
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18
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Ren L, Liu X, Huang X, Zhang H, Fei W, Yu X, Hu Z, Zhen Y, Chen S. Oxymatrine relieves high-fructose/fat-induced obesity via reprogramming the activity of lipid metabolism-related enhancer. Front Endocrinol (Lausanne) 2023; 14:1145575. [PMID: 37600712 PMCID: PMC10437059 DOI: 10.3389/fendo.2023.1145575] [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: 01/16/2023] [Accepted: 04/11/2023] [Indexed: 08/22/2023] Open
Abstract
Introduction Emerging evidence demonstrates that the high-fructose and high-fat diet (HFHF) induced obesity and fatty liver disease has become one of the most common metabolic disorders worldwide. Therefore, innovative investigations on compounds targeting obesity and fatty liver diseases are urgently needed. Methods The high-throughput natural compounds screen was performed to screen the important compounds. A rat HFHF model was constructed, the regulatory function of Oxymatrine in HFHF-induced obesity was further explored. Results We identified Oxymatrine, a natural compound extracted from Sophora flavescens, showed a potential compacity in high-fat diet-induced fatty liver disease. We found that oxymatrine significantly inhibited HFHF-induced obesity using a rat HFHF model. Additionally, we found that oxymatrine altered the enhancer landscape of subcutaneous adipose tissues by ChIP-seq analysis using antibodies against the H3K27ac histone modification. Motif enrichment analysis showed the Smad motif was significantly enriched in enhancers altered post-oxymatrine treatment. Further chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) analysis and luciferase reporter assays showed oxymatrine alters the binding of Smad3 on the enhancer regions of B-cell lymphoma 2 (Bcl2) and the enhancer activity of Bcl2. Discussion Together, our study highlighted oxymatrine could suppress high-fructose and high-fat diet-induced obesity by inhibiting the suppressor of mothers against decapentaplegic 3 (Smad3) binding on obesity-related enhancers.
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Affiliation(s)
- Luping Ren
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xuehua Liu
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
- Graduate School of Hebei North University, Zhangjiakou, Hebei, China
| | - Xitong Huang
- Department of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - He Zhang
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Wenjie Fei
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xian Yu
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Zhijuan Hu
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yunfeng Zhen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Shuchun Chen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
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He H, Zhong Y, Wang H, Tang PMK, Xue VW, Chen X, Chen J, Huang X, Wang C, Lan H. Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ. Int J Mol Sci 2023; 24:11396. [PMID: 37511155 PMCID: PMC10380492 DOI: 10.3390/ijms241411396] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/04/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Transforming growth factor-β (TGF-β)/Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases. However, the role of Smad3 in dyslipidemia and non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes remains unclear, and whether targeting Smad3 has a therapeutic effect on these metabolic abnormalities remains unexplored. These topics were investigated in this study in Smad3 knockout (KO)-db/db mice and by treating db/db mice with a Smad3-specific inhibitor SIS3. Compared to Smad3 wild-type (WT)-db/db mice, Smad3 KO-db/db mice were protected against dyslipidemia and NAFLD. Similarly, treatment of db/db mice with SIS3 at week 4 before the onset of type 2 diabetes until week 12 was capable of lowering blood glucose levels and improving diabetic dyslipidemia and NAFLD. In addition, using RNA-sequencing, the potential Smad3-target genes related to lipid metabolism was identified in the liver tissues of Smad3 KO/WT mice, and the regulatory mechanisms were investigated. Mechanistically, we uncovered that Smad3 targeted peroxisome proliferator-activated receptor delta (PPARδ) to induce dyslipidemia and NAFLD in db/db mice, which was improved by genetically deleting and pharmacologically inhibiting Smad3.
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Affiliation(s)
- Huijun He
- Division of Nephrology, Department of Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
| | - Yu Zhong
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Honglian Wang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Patrick Ming-Kuen Tang
- State Key Laboratory of Translational Oncology, Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Vivian Weiwen Xue
- State Key Laboratory of Translational Oncology, Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Xiaocui Chen
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jiaoyi Chen
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Xiaoru Huang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Cheng Wang
- Division of Nephrology, Department of Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
| | - Huiyao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
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20
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Xiao Y, Wang Y, Ryu J, Liu W, Zou H, Zhang R, Yan Y, Dai Z, Zhang D, Sun LZ, Liu F, Zhou Z, Dong LQ. Upregulated TGF-β1 contributes to hyperglycaemia in type 2 diabetes by potentiating glucagon signalling. Diabetologia 2023; 66:1142-1155. [PMID: 36917279 DOI: 10.1007/s00125-023-05889-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 01/12/2023] [Indexed: 03/16/2023]
Abstract
AIMS/HYPOTHESIS Glucagon-stimulated hepatic gluconeogenesis contributes to endogenous glucose production during fasting. Recent studies suggest that TGF-β is able to promote hepatic gluconeogenesis in mice. However, the physiological relevance of serum TGF-β levels to human glucose metabolism and the mechanism by which TGF-β enhances gluconeogenesis remain largely unknown. As enhanced gluconeogenesis is a signature feature of type 2 diabetes, elucidating the molecular mechanisms underlying TGF-β-promoted hepatic gluconeogenesis would allow us to better understand the process of normal glucose production and the pathophysiology of this process in type 2 diabetes. This study aimed to investigate the contribution of upregulated TGF-β1 in human type 2 diabetes and the molecular mechanism underlying the action of TGF-β1 in glucose metabolism. METHODS Serum levels of TGF-β1 were measured by ELISA in 74 control participants with normal glucose tolerance and 75 participants with type 2 diabetes. Human liver tissue was collected from participants without obesity and with or without type 2 diabetes for the measurement of TGF-β1 and glucagon signalling. To investigate the role of Smad3, a key signalling molecule downstream of the TGF-β1 receptor, in mediating the effect of TGF-β1 on glucagon signalling, we generated Smad3 knockout mice. Glucose levels in Smad3 knockout mice were measured during prolonged fasting and a glucagon tolerance test. Mouse primary hepatocytes were isolated from Smad3 knockout and wild-type (WT) mice to investigate the underlying molecular mechanisms. Smad3 phosphorylation was detected by western blotting, levels of cAMP were detected by ELISA and levels of protein kinase A (PKA)/cAMP response element-binding protein (CREB) phosphorylation were detected by western blotting. The dissociation of PKA subunits was measured by immunoprecipitation. RESULTS We observed higher levels of serum TGF-β1 in participants without obesity and with type 2 diabetes than in healthy control participants, which was positively correlated with HbA1c and fasting blood glucose levels. In addition, hyperactivation of the CREB and Smad3 signalling pathways was observed in the liver of participants with type 2 diabetes. Treating WT mouse primary hepatocytes with TGF-β1 greatly potentiated glucagon-stimulated PKA/CREB phosphorylation and hepatic gluconeogenesis. Mechanistically, TGF-β1 treatment induced the binding of Smad3 to the regulatory subunit of PKA (PKA-R), which prevented the association of PKA-R with the catalytic subunit of PKA (PKA-C) and led to the potentiation of glucagon-stimulated PKA signalling and gluconeogenesis. CONCLUSIONS/INTERPRETATION The hepatic TGF-β1/Smad3 pathway sensitises the effect of glucagon/PKA signalling on gluconeogenesis and synergistically promotes hepatic glucose production. Reducing serum levels of TGF-β1 and/or preventing hyperactivation of TGF-β1 signalling could be a novel approach for alleviating hyperglycaemia in type 2 diabetes.
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Affiliation(s)
- Yang Xiao
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yanfei Wang
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Endocrinology, The First People's Hospital of Foshan, Foshan, China
| | - Jiyoon Ryu
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Wei Liu
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Division of Biliopancreatic Surgery and Bariatric Surgery, Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hailan Zou
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Rong Zhang
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yin Yan
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhe Dai
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Deling Zhang
- Department of Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Lu-Zhe Sun
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Feng Liu
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
- Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
| | - Lily Q Dong
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA.
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21
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Maharjan BR, McLennan SV, Twigg SM, Williams PF. The Effect of TGFβ1 in Adipocyte on Inflammatory and Fibrotic Markers at Different Stages of Adipocyte Differentiation. PATHOPHYSIOLOGY 2022; 29:640-649. [PMID: 36548206 PMCID: PMC9788619 DOI: 10.3390/pathophysiology29040050] [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: 10/20/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022] Open
Abstract
Transforming growth factor beta (TGFβ) is a versatile cytokine. Although a profibrotic role of TGFβ is well established, its effect on tissue inhibitor of metalloproteinase (TIMPs) and inflammatory mediators are incompletely described. This study investigates the profibrotic and pro-inflammatory role of TGFβ1 during adipocyte differentiation. NIH3T3L1 cells were used for the in vitro study and were differentiated by adding a standard differentiation mix either with rosiglitazone (R-Diff) or without (S-Diff). Recombinant TGFβ1 (2 ng/mL) was added to the undifferentiated preadipocyte during the commitment stage and at the terminal differentiation stage. TGFβ1 treatment significantly decreased adiponectin mRNA at both early commitment (>300 fold) and terminal differentiated cells [S-Diff (~33%) or R-Diff (~20%)]. TGFβ1 upregulated collagen VI mRNA and its regulators connective tissue growth factor (CCN2/CTGF), TIMP1 and TIMP3 mRNA levels in undifferentiated preadipocytes and adipocytes at commitment stage. But in the terminal differentiated adipocytes, changes in mRNA and protein of collagen VI and TIMP3 mRNA were not observed despite an increase in CCN2/CTGF, TIMP1 mRNA. Although TGFβ1 upregulated interleukin-6 (IL6) and monocyte chemoattractant protein-1 (MCP1) mRNA at all stages of differentiation, decreased tumor necrosis factor-α (TNFα) mRNA was observed early in adipocyte differentiation. This study highlights the complex role of TGFβ1 on extracellular matrix (ECM) remodeling and inflammatory markers in stimulating both synthetic and inhibitory markers of fibrosis at different stages of adipocyte differentiation.
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Affiliation(s)
- Babu Raja Maharjan
- Greg Brown Diabetes & Endocrinology Laboratory, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia
- School of Medicine, Department of Biochemistry, Patan Academy of Health Sciences, Lalitpur 44700, Nepal
- Correspondence: (B.R.M.); (P.F.W.); Tel.: +61-2-8627-1889 (B.R.M. & P.F.W.)
| | - Susan V. McLennan
- Greg Brown Diabetes & Endocrinology Laboratory, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia
- New South Wales Health Pathology, Sydney, NSW 2050, Australia
| | - Stephen M. Twigg
- Greg Brown Diabetes & Endocrinology Laboratory, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW 2006, Australia
| | - Paul F. Williams
- Greg Brown Diabetes & Endocrinology Laboratory, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia
- Correspondence: (B.R.M.); (P.F.W.); Tel.: +61-2-8627-1889 (B.R.M. & P.F.W.)
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22
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D'Alessandro VF, Takeshita A, Yasuma T, Toda M, D'Alessandro-Gabazza CN, Okano Y, Tharavecharak S, Inoue C, Nishihama K, Fujimoto H, Kobayashi T, Yano Y, Gabazza EC. Transforming Growth Factorβ1 Overexpression Is Associated with Insulin Resistance and Rapidly Progressive Kidney Fibrosis under Diabetic Conditions. Int J Mol Sci 2022; 23:ijms232214265. [PMID: 36430743 PMCID: PMC9693927 DOI: 10.3390/ijms232214265] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 11/08/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022] Open
Abstract
Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The role of transforming growth factorβ1 in kidney fibrosis is undebatable. This study assessed whether the overexpression of transforming growth factorβ1 is associated with insulin resistance and the rapid progression of transforming growth factorβ1-mediated nephropathy under diabetic conditions. Diabetes mellitus was induced with streptozotocin in wild-type mice and transgenic mice with the kidney-specific overexpression of human transforming growth factorβ1. Mice treated with saline were the controls. Glucose tolerance and kidney fibrosis were evaluated. The blood glucose levels, the values of the homeostasis model assessment for insulin resistance, and the area of kidney fibrosis were significantly increased, and the renal function was significantly impaired in the diabetic transforming growth factorβ1 transgenic mice compared to the non-diabetic transgenic mice, diabetic wild-type mice, and non-diabetic mice. Transforming growth factorβ1 impaired the regulatory effect of insulin on glucose in the hepatocyte and skeletal muscle cell lines. This study shows that transforming growth factorβ1 overexpression is associated with insulin resistance and rapidly progressive kidney fibrosis under diabetic conditions in mice.
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Affiliation(s)
- Valeria Fridman D'Alessandro
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Atsuro Takeshita
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Taro Yasuma
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Masaaki Toda
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Corina N D'Alessandro-Gabazza
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Yuko Okano
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Suphachai Tharavecharak
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Chisa Inoue
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Kota Nishihama
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Hajime Fujimoto
- Department of Pulmonary and Critical care Medicine, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Tetsu Kobayashi
- Department of Pulmonary and Critical care Medicine, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Yutaka Yano
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
| | - Esteban C Gabazza
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu 514-8507, Japan
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23
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Earle A, Bessonny M, Benito J, Huang K, Parker H, Tyler E, Crawford B, Khan N, Armstrong B, Stamatikos A, Garimella S, Clay-Gilmour A. Urinary Exosomal MicroRNAs as Biomarkers for Obesity-Associated Chronic Kidney Disease. J Clin Med 2022; 11:5271. [PMID: 36142918 PMCID: PMC9502686 DOI: 10.3390/jcm11185271] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/24/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
The early detection of chronic kidney disease (CKD) is key to reducing the burden of disease and rising costs of care. This need has spurred interest in finding new biomarkers for CKD. Ideal bi-omarkers for CKD should be: easy to measure; stable; reliably detected, even when interfering substances are present; site-specific based on the type of injury (tubules vs. glomeruli); and its changes in concentration should correlate with disease risk or outcome. Currently, no single can-didate biomarker fulfills these criteria effectively, and the mechanisms underlying kidney fibrosis are not fully understood; however, there is growing evidence in support of microRNA-mediated pro-cesses. Specifically, urinary exosomal microRNAs may serve as biomarkers for kidney fibrosis. In-creasing incidences of obesity and the recognition of obesity-associated CKD have increased interest in the interplay of obesity and CKD. In this review, we provide: (1) an overview of the current scope of CKD biomarkers within obese individuals to elucidate the genetic pathways unique to obesi-ty-related CKD; (2) a review of microRNA expression in obese individuals with kidney fibrosis in the presence of comorbidities, such as diabetes mellitus and hypertension; (3) a review of thera-peutic processes, such as diet and exercise, that may influence miR-expression in obesity-associated CKD; (4) a review of the technical aspects of urinary exosome isolation; and (5) future areas of research.
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Affiliation(s)
- Angel Earle
- Department of Epidemiology & Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Madison Bessonny
- Department of Epidemiology & Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Josh Benito
- Prisma Health, Pediatric Nephrology, Greenville, SC 29615, USA
| | - Kun Huang
- Department of Food, Nutrition, and Packaging Sciences, College of Agriculture, Forestry & Life Sciences, Clemson University, Clemson, SC 29634, USA
| | - Hannah Parker
- Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Emily Tyler
- Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Brittany Crawford
- Department of Epidemiology & Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Nabeeha Khan
- Department of Epidemiology & Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Bridget Armstrong
- Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Alexis Stamatikos
- Department of Food, Nutrition, and Packaging Sciences, College of Agriculture, Forestry & Life Sciences, Clemson University, Clemson, SC 29634, USA
| | - Sudha Garimella
- Prisma Health, Pediatric Nephrology, Greenville, SC 29615, USA
| | - Alyssa Clay-Gilmour
- Department of Epidemiology & Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
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24
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The effects of brewers' spent grain on high-fat diet-induced fatty liver. Biochem Biophys Res Commun 2022; 616:49-55. [PMID: 35636255 DOI: 10.1016/j.bbrc.2022.05.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/09/2022] [Accepted: 05/15/2022] [Indexed: 11/20/2022]
Abstract
Obesity drives nonalcoholic fatty liver disease (NAFLD). This study investigated the effects of dietary brewers' spent grain (BSG) supplementation on obesity-induced NAFLD. Mice fed a high-fat diet supplemented with 30% BSG (HFD30) had reduced body weight and decreased plasma total cholesterol (TC) concentrations compared with HFD-fed mice. Retroperitoneal white adipose tissue (RWAT) and liver weights were reduced. Consistent with reduced hepatic triacylglycerol, TC, and non-esterified fatty acid concentrations, HFD30-fed mice showed reduced hepatic steatosis. 3-hydroxy-3-methylglutaryl-CoA reductase and low-density lipoprotein receptor genes were increased, whereas carnitine palmitoyltransferase 1 alpha, ATP-binding cassette subfamily A member 1 (Abca1), and cholesterol 7 alpha-hydroxylase genes were upregulated in the liver of HFD30-fed mice. Abca1 gene expression was also increased in epididymal WAT and RWAT of HFD30-fed mice. BSG supplementation increased and decreased fecal fat and bile acid concentrations, respectively. Taken together, BSG supplementation reduced HFD-induced hepatic lipid accumulation by increasing fatty acid oxidation and bile acid synthesis in the liver as well as decreasing lipid absorption in the intestine.
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25
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Zou J, Zhou X, Chen X, Ma Y, Yu R. Shenkang Injection for Treating Renal Fibrosis-Metabonomics and Regulation of E3 Ubiquitin Ligase Smurfs on TGF-β/Smads Signal Transduction. Front Pharmacol 2022; 13:849832. [PMID: 35721120 PMCID: PMC9201572 DOI: 10.3389/fphar.2022.849832] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 04/25/2022] [Indexed: 12/31/2022] Open
Abstract
At present, TGF-β is the most critical fibrogenic factor known. Smad ubiquitin ligase Smurfs play an important role in the regulation of the TGF-/Smads signaling pathway, which is linked to metabolite changes in renal fibrosis. Previous studies have shown that Shenkang injection can prevent and treat chronic kidney disease through multiple channels of action. However, the precise relationship between Shenkang injection and the regulation of the TGF-/Smads signaling pathway in the treatment of chronic kidney disease is unknown. Here, we evaluated the pharmacological effects of Shenkang injection on ubiquitination and metabolic changes of the TGF-β/Smads signaling pathway in UUO mice using pathology-related indicators, immunoprecipitation, subcellular co-location, and metabonomics analysis. Our findings indicate that Shenkang injection can promote nuclear translocation of Smurf1 and Smurf2 to TGF- membrane receptors TR-I and Smad2 and ubiquitinated degradation of these proteins. Furthermore, the formation of TβR-I/TβR-II, TβR-I/Smad2, and TβR-I/Smad3 complexes was inhibited to negatively regulate the TGF-β/Smad signaling pathway induced renal tubular epithelial transdifferentiation (EMT). The EMT process is not very relevant in vivo, although it is clear that TGF-β induces EMT in cultured cells, which has been demonstrated by numerous teams around the world. However, this is not the case with the in vivo models of kidney fibrosis, especially UUO. In addition, Shenkang injection can improve amino acid metabolism, purine metabolism, and fatty acid metabolism disorders.
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Affiliation(s)
- Junju Zou
- Hunan Provincial Key Laboratory of Translational Research in TCM Prescriptions and Zheng, Hunan University of Chinese Medicine, Changsha, China
| | - Xiaotao Zhou
- School of Basic Medicine, Chengdu University of Chinese Medicine, Chengdu, China
| | - Xian Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuerong Ma
- School of Basic Medicine, Chengdu University of Chinese Medicine, Chengdu, China
| | - Rong Yu
- Hunan Provincial Key Laboratory of Translational Research in TCM Prescriptions and Zheng, Hunan University of Chinese Medicine, Changsha, China
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26
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Xiang X, Ohshiro K, Zaidi S, Yang X, Bhowmick K, Vegesna AK, Bernstein D, Crawford JM, Mishra B, Latham PS, Gough NR, Rao S, Mishra L. Impaired reciprocal regulation between SIRT6 and TGF-β signaling in fatty liver. FASEB J 2022; 36:e22335. [PMID: 35506565 PMCID: PMC11288617 DOI: 10.1096/fj.202101518r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 03/14/2022] [Accepted: 04/21/2022] [Indexed: 11/11/2022]
Abstract
Dysregulated transforming growth factor-beta (TGF-β) signaling contributes to fibrotic liver disease and hepatocellular cancer (HCC), both of which are associated with fatty liver disease. SIRT6 limits fibrosis by inhibiting TGF-β signaling through deacetylating SMAD2 and SMAD3 and limits lipogenesis by inhibiting SREBP1 and SREBP2 activity. Here, we showed that, compared to wild-type mice, high-fat diet-induced fatty liver is worse in TGF-β signaling-deficient mice (SPTBN1+/- ) and the mutant mice had reduced SIRT6 abundance in the liver. Therefore, we hypothesized that altered reciprocal regulation between TGF-β signaling and SIRT6 contributes to these liver pathologies. We found that deficiency in SMAD3 or SPTBN1 reduced SIRT6 mRNA and protein abundance and impaired TGF-β induction of SIRT6 transcripts, and that SMAD3 bound to the SIRT6 promoter, suggesting that an SMAD3-SPTBN1 pathway mediated the induction of SIRT6 in response to TGF-β. Overexpression of SIRT6 in HCC cells reduced the expression of TGF-β-induced genes, consistent with the suppressive role of SIRT6 on TGF-β signaling. Manipulation of SIRT6 abundance in HCC cells altered sterol regulatory element-binding protein (SREBP) activity and overexpression of SIRT6 reduced the amount of acetylated SPTBN1 and the abundance of both SMAD3 and SPTBN1. Furthermore, induction of SREBP target genes in response to SIRT6 overexpression was impaired in SPTBN1 heterozygous cells. Thus, we identified a regulatory loop between SIRT6 and SPTBN1 that represents a potential mechanism for susceptibility to fatty liver in the presence of dysfunctional TGF-β signaling.
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Affiliation(s)
- Xiyan Xiang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Kazufumi Ohshiro
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - Sobia Zaidi
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Xiaochun Yang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Krishanu Bhowmick
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Anil K. Vegesna
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - David Bernstein
- Division of Hepatology, Northwell Health and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - James M Crawford
- Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Bibhuti Mishra
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Department of Neurology, Northwell Health, Manhasset, NY, 11030, USA
| | - Patricia S. Latham
- Department of Pathology, George Washington University, Washington, DC, 20037, USA
| | - Nancy R. Gough
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - Shuyun Rao
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
- Division of Gastroenterology, Department of Medicine, Northwell Health, NY, 11030, USA
- Department of Surgery, The George Washington University, Washington, DC, 20037, USA
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27
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Zhao J, Hu L, Gui W, Xiao L, Wang W, Xia J, Fan H, Li Z, Zhu Q, Hou X, Chu H, Seki E, Yang L. Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p. Hepatol Commun 2022; 6:1301-1321. [PMID: 35018737 PMCID: PMC9134819 DOI: 10.1002/hep4.1892] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 12/06/2021] [Accepted: 12/18/2021] [Indexed: 01/18/2023] Open
Abstract
Transforming growth factor beta (TGF-β) signaling in hepatocytes promotes steatosis and body weight gain. However, processes that TGF-β signaling in hepatocytes promote pathological body weight gain in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. Obesity and NAFLD were induced by 16 weeks of feeding a high-fat diet (HFD) in hepatocyte-specific TGF-β receptor II-deficient (Tgfbr2ΔHEP ) and Tgfbr2flox/flox mice. In addition, browning of white adipose tissue (WAT) was induced by administration of CL-316,243 (a β3-adrenergic agonist) or cold exposure for 7 days. Compared with Tgfbr2 flox/flox mice, Tgfbr2ΔHEP mice were resistant to steatosis and obesity. The metabolic changes in Tgfbr2ΔHEP mice were due to the increase of mitochondrial oxidative phosphorylation in the liver and white-to-beige fat conversion. A further mechanistic study revealed that exosomal let-7b-5p derived from hepatocytes was robustly elevated after stimulation with palmitic acid and TGF-β. Indeed, let-7b-5p levels were low in the liver, serum exosomes, inguinal WAT, and epididymal WAT in HFD-fed Tgfbr2ΔHEP mice. Moreover, 3T3-L1 cells internalized hepatocyte-derived exosomes. An in vitro experiment demonstrated that let-7b-5p overexpression increased hepatocyte fatty acid transport and inhibited adipocyte-like cell thermogenesis, whereas let-7b-5p inhibitor exerted the opposite effects. Conclusion: Hepatocyte TGF-β-let-7b-5p signaling promotes HFD-induced steatosis and obesity by reducing mitochondrial oxidative phosphorylation and suppressing white-to-beige fat conversion. This effect of hepatocyte TGF-β signaling in metabolism is partially associated with exosomal let-7b-5p.
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Affiliation(s)
- Jinfang Zhao
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Lilin Hu
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Wenfang Gui
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Li Xiao
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Weijun Wang
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jing Xia
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Huiqian Fan
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Zhonglin Li
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | | | - Xiaohua Hou
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Huikuan Chu
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Ekihiro Seki
- Karsh Division of Gastroenterology and HepatologyCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Ling Yang
- Division of GastroenterologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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28
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Losartan ameliorates renal interstitial fibrosis through metabolic pathway and Smurfs-TGF-β/Smad. Biomed Pharmacother 2022; 149:112931. [PMID: 36068784 DOI: 10.1016/j.biopha.2022.112931] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 03/27/2022] [Accepted: 04/05/2022] [Indexed: 11/22/2022] Open
Abstract
The genesis and development of renal fibrosis involve a variety of pathways closely related to inflammation, cytokines, oxidative stress and metabolic abnormalities. Renal fibrosis is the result of a complex combination of a variety of lesions. Epithelial-mesenchymal transdifferentiation (EMT) of renal tubular epithelial cells is considered the key to renal fibrosis. Losartan is a typical Angiotensin II (ANG II) receptor antagonist and relaxes blood vessels. In this study, we investigated the effects of losartan on Unilateral Ureteral Obstruction (UUO) model mice by studying the changes in the TGF-β/Smad and metabolomics. Male C57BL/6 J mice were intervened with the UUO model and given losartan (10, 20, 30 mg/kg/d) for 28 consecutive days. The results showed that losartan could reduce UUO-induced abnormal serum metabolic spectrum and renal function. It could also improve renal tubular-interstitial injury and fibrosis by reducing tubulointerstitial dilation and collagen deposition. In addition, losartan promoted the expression of Smurf2 and Smurf1, i.e., Smad7 and E3 ubiquitin-linked enzymes, in the nucleus to degrade the type I receptor of TGF-β1 (TβR-I) and P-Smad2/3 to inhibit renal tubular epithelial cells EMT. In summary, these findings indicated that losartan could regulate the TGF-β/Smad and metabolic pathway in UUO model mice through ubiquitination to reduce renal fibrosis.
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29
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Crouse WL, Das SK, Le T, Keele G, Holl K, Seshie O, Craddock A, Sharma NK, Comeau ME, Langefeld C, Hawkins GA, Mott R, Valdar W, Solberg Woods LC. Transcriptome-wide analyses of adipose tissue in outbred rats reveal genetic regulatory mechanisms relevant for human obesity. Physiol Genomics 2022; 54:206-219. [PMID: 35467982 DOI: 10.1152/physiolgenomics.00172.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Transcriptomic analysis in metabolically active tissues allows a systems genetics approach to identify causal genes and networks involved in metabolic disease. Outbred heterogeneous stock (HS) rats are used for genetic mapping of complex traits, but to-date, a systems genetics analysis of metabolic tissues has not been done. We investigated whether adiposity-associated genes and gene co-expression networks in outbred heterogeneous stock (HS) rats overlap those found in humans. We analyzed RNAseq data from adipose tissue of 415 male HS rats, correlated these transcripts with body weight (BW) and compared transcriptome signatures to two human cohorts: the "African American Genetics of Metabolism and Expression" and "Metabolic Syndrome in Men". We used weighted gene co-expression network analysis to identify adiposity-associated gene networks and mediation analysis to identify genes under genetic control whose expression drives adiposity. We identified 554 orthologous "consensus genes" whose expression correlates with BW in the rat and with body mass index (BMI) in both human cohorts. Consensus genes fell within eight co-expressed networks and were enriched for genes involved in immune system function, cell growth, extracellular matrix organization and lipid metabolic processes. We identified 19 consensus genes for which genetic variation may influence BW via their expression, including those involved in lipolysis (e.g., Hcar1), inflammation (e.g., Rgs1), adipogenesis (e.g., Tmem120b) or no previously known role in obesity (e.g., St14, Msa4a6). Strong concordance between HS rat and human BW/BMI associated transcripts demonstrates translational utility of the rat model, while identification of novel genes expands our knowledge of the genetics underlying obesity.
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Affiliation(s)
- Wesley L Crouse
- University of North Carolina at Chapel Hill, Department of Genetics, Chapel Hill, NC, United States
| | - Swapan Kumar Das
- Wake Forest University School of Medicine, Department of Internal Medicine, Winston Salem, NC, United States
| | - Thu Le
- University College London, Department of Genetics, Evolution and Environment, Division of Biosciences, London, United Kingdom
| | - Gregory Keele
- Jackson Laboratories, Roux Center for Genomics and Computational Biology, Bar Harbor, ME, United States
| | - Katie Holl
- Medical College of Wisconsin, Department of Pediatrics, Milwaukee, WI, United States
| | - Osborne Seshie
- Wake Forest University School of Medicine, Department of Internal Medicine, Winston Salem, NC, United States
| | - Ann Craddock
- Wake Forest University School of Medicine, Department of Biochemistry, Winston Salem, NC, United States
| | - Neeraj Kumar Sharma
- Wake Forest University School of Medicine, Department of Internal Medicine, Winston Salem, NC, United States
| | - Mary Elizabeth Comeau
- Wake Forest University School of Medicine, Department of Biostatistics and Data Sciences, Winston Salem, NC, United States
| | - Carl Langefeld
- Wake Forest University School of Medicine, Department of Biostatistics and Data Sciences, Winston Salem, NC, United States
| | - Gregory A Hawkins
- Wake Forest University School of Medicine, Department of Biochemistry, Winston Salem, NC, United States
| | - Richard Mott
- University College London, Department of Genetics, Evolution and Environment, Division of Biosciences, London, United Kingdom
| | - William Valdar
- University of North Carolina at Chapel Hill, Department of Genetics, Chapel Hill, NC, United States
| | - Leah C Solberg Woods
- Wake Forest University School of Medicine, Department of Internal Medicine, Winston Salem, NC, United States
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30
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Guo X, Sunil C, Qian G. Obesity and the Development of Lung Fibrosis. Front Pharmacol 2022; 12:812166. [PMID: 35082682 PMCID: PMC8784552 DOI: 10.3389/fphar.2021.812166] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/16/2021] [Indexed: 12/20/2022] Open
Abstract
Obesity is an epidemic worldwide and the obese people suffer from a range of respiratory complications including fibrotic changes in the lung. The influence of obesity on the lung is multi-factorial, which is related to both mechanical injury and various inflammatory mediators produced by excessive adipose tissues, and infiltrated immune cells. Adiposity causes increased production of inflammatory mediators, for example, cytokines, chemokines, and adipokines, both locally and in the systemic circulation, thereby rendering susceptibility to respiratory diseases, and altered responses. Lung fibrosis is closely related to chronic inflammation in the lung. Current data suggest a link between lung fibrosis and diet-induced obesity, although the mechanism remains incomplete understood. This review summarizes findings on the association of lung fibrosis with obesity, highlights the role of several critical inflammatory mediators (e.g., TNF-α, TGF-β, and MCP-1) in obesity related lung fibrosis and the implication of obesity in the outcomes of idiopathic pulmonary fibrosis patients.
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Affiliation(s)
- Xia Guo
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, The University of Texas at Tyler, Tyler, TX, United States
| | - Christudas Sunil
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, The University of Texas at Tyler, Tyler, TX, United States
| | - Guoqing Qian
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, The University of Texas at Tyler, Tyler, TX, United States
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31
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Timmons JA, Anighoro A, Brogan RJ, Stahl J, Wahlestedt C, Farquhar DG, Taylor-King J, Volmar CH, Kraus WE, Phillips SM. A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease. eLife 2022; 11:68832. [PMID: 35037854 PMCID: PMC8763401 DOI: 10.7554/elife.68832] [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: 03/26/2021] [Accepted: 11/26/2021] [Indexed: 12/22/2022] Open
Abstract
Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.
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Affiliation(s)
- James A Timmons
- William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.,Augur Precision Medicine LTD, Stirling, United Kingdom
| | | | | | - Jack Stahl
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, United States
| | - Claes Wahlestedt
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, United States
| | | | | | - Claude-Henry Volmar
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, United States
| | | | - Stuart M Phillips
- Faculty of Science, Kinesiology, McMaster University, Hamilton, Canada
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32
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Rao S, Yang X, Ohshiro K, Zaidi S, Wang Z, Shetty K, Xiang X, Hassan I, Mohammad T, Latham PS, Nguyen BN, Wong L, Yu H, Al-Abed Y, Mishra B, Vacca M, Guenigault G, Allison MED, Vidal-Puig A, Benhammou JN, Alvarez M, Pajukanta P, Pisegna JR, Mishra L. β2-spectrin (SPTBN1) as a therapeutic target for diet-induced liver disease and preventing cancer development. Sci Transl Med 2021; 13:eabk2267. [PMID: 34910547 PMCID: PMC8941321 DOI: 10.1126/scitranslmed.abk2267] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The prevalence of nonalcoholic steatohepatitis (NASH) and liver cancer is increasing. De novo lipogenesis and fibrosis contribute to disease progression and cancerous transformation. Here, we found that β2-spectrin (SPTBN1) promotes sterol regulatory element (SRE)–binding protein (SREBP)–stimulated lipogenesis and development of liver cancer in mice fed a high-fat diet (HFD) or a western diet (WD). Either hepatocyte-specific knockout of SPTBN1 or siRNA-mediated therapy protected mice from HFD/WD-induced obesity and fibrosis, lipid accumulation, and tissue damage in the liver. Biochemical analysis suggested that HFD/WD induces SPTBN1 and SREBP1 cleavage by CASPASE-3 and that the cleaved products interact to promote expression of genes with sterol response elements. Analysis of human NASH tissue revealed increased SPTBN1 and CASPASE-3 expression. Thus, our data indicate that SPTBN1 represents a potential target for therapeutic intervention in NASH and liver cancer.
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Affiliation(s)
- Shuyun Rao
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
| | - Xiaochun Yang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Kazufumi Ohshiro
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Sobia Zaidi
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Zhanhuai Wang
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Kirti Shetty
- Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, 21201, USA
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Patricia S. Latham
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
- Department of Pathology, The George Washington University, DC, 20037, USA
| | - Bao-Ngoc Nguyen
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
| | - Linda Wong
- Cancer Biology department, University of Hawaii Cancer Center, HI, 96813, USA
- Dept of Surgery, University of Hawaii John A. Burns School of Medicine, HI, 96813, USA
| | - Herbert Yu
- Epidemiology Program, University of Hawaii Cancer Center, HI, 96813, USA
| | - Yousef Al-Abed
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Bibhuti Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
- Department of Neurology, Northwell Health, Manhasset, NY, 11030, USA
| | - Michele Vacca
- TVP Lab, Metabolic Research Laboratories, WT/MRC Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom
| | | | - Michael ED Allison
- Liver Unit, Cambridge Biomedical Research Centre, Cambridge University Hospitals, CB2 0QQ, United Kingdom
| | - Antonio Vidal-Puig
- TVP Lab, Metabolic Research Laboratories, WT/MRC Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom
- Welcome Trust Sanger Institute, Hinxton, CB10 1SA, United Kingdom
- Cambridge University Nanjing Centre of Technology and Innovation, Jiangbei Area, Nanjing, 210000, China
| | - Jihane N Benhammou
- Vatche and Tamar Manoukian Division of Digestive Diseases and Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, CA, 90095, USA
| | - Marcus Alvarez
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
- Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Joseph R. Pisegna
- Department of Medicine and Human Genetics, Division of Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, CA, 90095, USA
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
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33
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Pahk K, Lee SG, Joung C, Kim EO, Kwon HW, Kim DH, Hwang JI, Kim S, Kim WK. SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice. Biomed Pharmacother 2021; 145:112441. [PMID: 34813997 DOI: 10.1016/j.biopha.2021.112441] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/08/2021] [Accepted: 11/16/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Obesity-induced inflamed visceral adipose tissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-associated nonalcoholic fatty liver disease (NAFLD). Transforming growth factor (TGF)-β /Smad3 signaling plays a crucial role in the inflammatory events within the VAT. Here, we investigate whether SP-1154, a novel synthetic verbenone derivative, can inhibit TGF-β/Smad3 signaling thereby exhibiting a therapeutic effect against obesity-induced inflamed VAT and subsequent NAFLD in high-fat diet-induced mice. METHODS NAFLD was induced by a high-fat diet (60% fat) for 20 weeks using the male C57BL/6 mice. SP-1154 (50 mg/kg) was orally given daily for 20 weeks. In vivo VAT- and systemic inflammation were measured by using 18F-fluorodeoxyglucose positron emission tomography and C-reactive protein levels. Both insulin tolerance- and glucose tolerance test were performed to assess the status of insulin resistance and glucose intolerance. Histological and molecular analyses were performed on harvested liver and VAT. KEY FINDINGS SP-1154 inhibited TGF-β/Smad3 signaling pathway and remarkably suppressed high-fat diet-induced VAT inflammation and its related systemic inflammation. Furthermore, SP-1154 significantly improved insulin sensitivity with glucose homeostasis and reduced hepatic steatosis. SP-1154 significantly improves VAT inflammation and obesity-related NAFLD. CONCLUSION Our novel findings support the potential use of SP-1154 as a therapeutic drug for obesity and its related NAFLD by targeting the inflamed VAT.
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Affiliation(s)
- Kisoo Pahk
- Department of Nuclear Medicine, Korea University Anam Hospital, Seoul, South Korea
| | - Sang Gil Lee
- Institute for Inflammation Control, Korea University, Seoul, South Korea; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Chanmin Joung
- Institute for Inflammation Control, Korea University, Seoul, South Korea
| | - Eun-Ok Kim
- Medcial Science Research Center, College of Medicine, Korea University, Seoul, South Korea
| | - Hyun Woo Kwon
- Department of Nuclear Medicine, Korea University Anam Hospital, Seoul, South Korea
| | - Dong Hwi Kim
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, South Korea
| | - Jong-Ik Hwang
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, South Korea
| | - Sungeun Kim
- Department of Nuclear Medicine, Korea University Anam Hospital, Seoul, South Korea
| | - Won-Ki Kim
- Institute for Inflammation Control, Korea University, Seoul, South Korea.
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34
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Kumari R, Irudayam MJ, Al Abdallah Q, Jones TL, Mims TS, Puchowicz MA, Pierre JF, Brown CW. SMAD2 and SMAD3 differentially regulate adiposity and the growth of subcutaneous white adipose tissue. FASEB J 2021; 35:e22018. [PMID: 34731499 DOI: 10.1096/fj.202101244r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/28/2021] [Accepted: 10/13/2021] [Indexed: 11/11/2022]
Abstract
Adipose tissue is the primary site of energy storage, playing important roles in health. While adipose research largely focuses on obesity, fat also has other critical functions, producing adipocytokines and contributing to normal nutrient metabolism, which in turn play important roles in satiety and total energy homeostasis. SMAD2/3 proteins are downstream mediators of activin signaling, which regulate critical preadipocyte and mature adipocyte functions. Smad2 global knockout mice exhibit embryonic lethality, whereas global loss of Smad3 protects mice against diet-induced obesity. The direct contributions of Smad2 and Smad3 in adipose tissues, however, are unknown. Here, we sought to determine the primary effects of adipocyte-selective reduction of Smad2 or Smad3 on diet-induced adiposity using Smad2 or Smad3 "floxed" mice intercrossed with Adiponectin-Cre mice. Additionally, we examined visceral and subcutaneous preadipocyte differentiation efficiency in vitro. Almost all wild type subcutaneous preadipocytes differentiated into mature adipocytes. In contrast, visceral preadipocytes differentiated poorly. Exogenous activin A suppressed differentiation of preadipocytes from both depots. Smad2 conditional knockout (Smad2cKO) mice did not exhibit significant effects on weight gain, irrespective of diet, whereas Smad3 conditional knockout (Smad3cKO) male mice displayed a trend of reduced body weight on high-fat diet. On both diets, Smad3cKO mice displayed an adipose depot-selective phenotype, with a significant reduction in subcutaneous fat mass but not visceral fat mass. Our data suggest that Smad3 is an important contributor to the maintenance of subcutaneous white adipose tissue in a sex-selective fashion. These findings have implications for understanding SMAD-mediated, depot selective regulation of adipocyte growth and differentiation.
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Affiliation(s)
- Roshan Kumari
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.,Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Maria Johnson Irudayam
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Qusai Al Abdallah
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Tamekia L Jones
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.,Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.,Children's Foundation Research Institute, Memphis, Tennessee, USA
| | - Tahliyah S Mims
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Michelle A Puchowicz
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Joseph F Pierre
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Chester W Brown
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.,Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.,Le Bonheur Children's Hospital, Memphis, Tennessee, USA
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35
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Role of Inflammatory Cytokines, Growth Factors and Adipokines in Adipogenesis and Insulin Resistance. Inflammation 2021; 45:31-44. [PMID: 34536157 PMCID: PMC8449520 DOI: 10.1007/s10753-021-01559-z] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/24/2021] [Accepted: 08/31/2021] [Indexed: 01/06/2023]
Abstract
Obesity, manifested by increased adiposity, represents a main cause of morbidity in the developed countries, causing increased risk of insulin resistance and type 2 diabetes mellitus. Recruitment of macrophages and activation of innate immunity represent the initial insult, which can be further exacerbated through secretion of chemokines and adipocytokines from activated macrophages and other cells within the adipose tissue. These events can impact adipogenesis, causing dysfunction of the adipose tissue and increased risk of insulin resistance. Various factors mediate adiposity and related insulin resistance including inflammatory and non-inflammatory factors such as pro and anti-inflammatory cytokines, adipokines and growth factors. In this review we will discuss the role of these factors in adipogenesis and development of insulin resistance and type 2 diabetes mellitus in the context of obesity. Understanding the molecular mechanisms that mediate adipogenesis and insulin resistance could help the development of novel therapeutic strategies for individuals at higher risk of insulin resistance and type 2 diabetes mellitus.
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36
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Makowski LM, Leffers M, Waltenberger J, Pardali E. Transforming growth factor-β1 signalling triggers vascular endothelial growth factor resistance and monocyte dysfunction in type 2 diabetes mellitus. J Cell Mol Med 2021; 25:5316-5325. [PMID: 33942489 PMCID: PMC8178271 DOI: 10.1111/jcmm.16543] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 03/07/2021] [Accepted: 03/24/2021] [Indexed: 12/01/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) leads to monocyte dysfunction associated with atherogenesis and defective arteriogenesis. Transforming growth factor (TGF)-β1, placenta growth factor (PlGF)-1 and vascular endothelial growth factor (VEGF)A play important roles in atherogenesis and arteriogenesis. VEGF-receptor (VEGFR)-mediated monocyte migration is inhibited in T2DM (VEGFA resistance), while TGF-β1-induced monocyte migration is fully functional. Therefore, we hypothesize that TGF-β antagonises the VEGFA responses in human monocytes. We demonstrate that monocytes from T2DM patients have an increased migratory response towards low concentrations of TGF-β1, while PlGF-1/VEGFA responses are mitigated. Mechanistically, this is due to increased expression of type II TGF-β receptor in monocytes under high-glucose conditions and increased expression of soluble (s)VEGFR1, which is known to interfere with VEGFA signalling. VEGFA resistance in monocytes from T2DM patients can be rescued by either experimental down-regulation of TGF-β receptor expression in vitro or by functional blocking of TGF-β signalling using either a TGF-β receptor kinase inhibitor or a TGF-β neutralizing antibody. Our data demonstrate that both T2DM and high-glucose potentiate the TGF-β pathway. TGF-β signalling impairs VEGFR-mediated responses in T2DM monocytes and in this way contributes to mononuclear cell dysfunction, provide novel insights into T2DM vascular dysfunction.
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Affiliation(s)
- Lena-Maria Makowski
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Cardiolology, Münster, Germany
| | - Merle Leffers
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Cardiolology, Münster, Germany
| | - Johannes Waltenberger
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Cardiolology, Münster, Germany.,Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Münster, Germany.,Department of Cardiovascular Medicine, Medical Faculty, University of Münster, Münster, Germany
| | - Evangelia Pardali
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Cardiolology, Münster, Germany.,Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Münster, Germany
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The effect of TGFβ1 on thermogenic markers is dependent on the degree of adipocyte differentiation. Biosci Rep 2021; 40:223097. [PMID: 32352511 PMCID: PMC7225410 DOI: 10.1042/bsr20194262] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 04/15/2020] [Accepted: 04/27/2020] [Indexed: 12/02/2022] Open
Abstract
Transforming growth factor β (TGFβ) a multifunctional cytokine is known to regulate cell proliferation, differentiation, migration and survival. Although there is variable expression of modulators of TGFβ action during differentiation, a differential effect on fat cell metabolism at the different stages of adipocyte differentiation was unclear. In the present study, 3T3L1 cells were used as an in vitro model to study the effect of TGFβ on adipogenic and thermogenic markers at various stages of preadipocyte to mature adipocyte differentiation. As in our earlier studies on the effect of TGFβ on CEBP’s, we used a standard differentiation mix, and one with the addition of rosiglitazone. RhTGFβ1 was added to undifferentiated adipocytes (preadipocytes) and to adipocytes at day 0 (commitment stage) as well as day 10 (terminal differentiation). Cellular responses in terms of Pref1, PPARγ, TLE3, PGC1α, PRDM16, UCP1 and UCP2 mRNA levels and selected protein products, were determined. Increases in PPARγ, PRDM16, UCP1 and UCP2 mRNA and decreases in Pref1 are good indicators of successful differentiation. The early addition of rhTGFβ1 during commitment stage decreased PPARγ, PRDM16, TLE3, UCP1 and UCP2 mRNA and decreased PRDM16 protein consistent with our earlier report on the inhibition of CEBP’s by TGFβ and CCN2. The addition of rhTGFβ1 to mature adipocyte at day 10 increased UCP1 mRNA and increased PRDM16 and UCP1 proteins. In the present study, our results suggest that TGFβ1 added late enhances the thermogenic potential of mature cells and causes 3T3L1 cells to differentiate to resemble brown or beige rather than white adipose tissue.
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Lei Z, Wu H, Xiong Y, Wei D, Wang X, Luoreng Z, Cai X, Ma Y. ncRNAs regulate bovine adipose tissue deposition. Mol Cell Biochem 2021; 476:2837-2845. [PMID: 33730298 DOI: 10.1007/s11010-021-04132-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/06/2021] [Indexed: 12/13/2022]
Abstract
Lipid metabolism, which encompasses synthesis and degradation of lipids, is critical for a wide range of cellular functions, including structural and morphological properties of organelles, energy storage, signalling, and the stability and function of membrane proteins. Adipose tissue is a dynamic tissue type that performs a lot of significant physiological functions, including secretion, and is involved in maintaining homeostasis and in regulatory roles of other tissues based on paracrine or endocrine. More recently, several classes of non-coding RNAs (ncRNAs), such as long non-coding RNA (lncRNA), microRNA (miRNA) and circular RNA (circRNA), have been discovered in adipocytes, and they act as critical regulators of gene expression in adipogenesis and regulate adipogenesis through multiple pathways. In the present paper, we discussed several classes of non-coding RNAs and summarized the latest research on the regulatory role of ncRNAs in bovine adipogenesis. We gave examples for known modes of action to look forward to providing reference information future scientific research in cattle breeding.
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Affiliation(s)
- Zhaoxiong Lei
- School of Agriculture, Ningxia University, YinChuan, China.,Key Laboratory of Ruminant Molecular and Cellular Breeding, Ningxia University, Ningxia Hui Autonomous Region, YinChuan, China
| | - Huiguang Wu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Yan Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Dawei Wei
- School of Agriculture, Ningxia University, YinChuan, China.,Key Laboratory of Ruminant Molecular and Cellular Breeding, Ningxia University, Ningxia Hui Autonomous Region, YinChuan, China
| | - Xingping Wang
- School of Agriculture, Ningxia University, YinChuan, China.,Key Laboratory of Ruminant Molecular and Cellular Breeding, Ningxia University, Ningxia Hui Autonomous Region, YinChuan, China
| | - Zhuoma Luoreng
- School of Agriculture, Ningxia University, YinChuan, China.,Key Laboratory of Ruminant Molecular and Cellular Breeding, Ningxia University, Ningxia Hui Autonomous Region, YinChuan, China
| | - Xiaoyan Cai
- School of Agriculture, Ningxia University, YinChuan, China.,Key Laboratory of Ruminant Molecular and Cellular Breeding, Ningxia University, Ningxia Hui Autonomous Region, YinChuan, China
| | - Yun Ma
- School of Agriculture, Ningxia University, YinChuan, China. .,Key Laboratory of Ruminant Molecular and Cellular Breeding, Ningxia University, Ningxia Hui Autonomous Region, YinChuan, China. .,College of Life Science, Xinyang Normal University, Xinyang, China.
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Woo J, Koziol-White C, Panettieri R, Jude J. TGF-β: The missing link in obesity-associated airway diseases? CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100016. [PMID: 34909651 PMCID: PMC8663968 DOI: 10.1016/j.crphar.2021.100016] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/15/2021] [Accepted: 01/20/2021] [Indexed: 01/19/2023] Open
Abstract
Obesity is emerging as a global public health epidemic. The co-morbidities associated with obesity significantly contribute to reduced quality of life, mortality, and global healthcare burden. Compared to other asthma comorbidities, obesity prominently engenders susceptibility to inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), contributes to greater disease severity and evokes insensitivity to current therapies. Unlike in other metabolic diseases associated with obesity, the mechanistic link between obesity and airway diseases is only poorly defined. Transforming growth factor-β (TGF-β) is a pleiotropic inflammatory cytokine belonging to a family of growth factors with pivotal roles in asthma. In this review, we summarize the role of TGF-β in major obesity-associated co-morbidities to shed light on mechanisms of the diseases. Literature evidence shows that TGF-β mechanistically links many co-morbidities with obesity through its profibrotic, remodeling, and proinflammatory functions. We posit that TGF-β plays a similar mechanistic role in obesity-associated inflammatory airway diseases such as asthma and COPD. Concerning the role of TGF-β on metabolic effects of obesity, we posit that TGF-β has a similar mechanistic role in obesity-associated inflammatory airway diseases in interplay with different comorbidities such as hypertension, metabolic diseases like type 2 diabetes, and cardiomyopathies. Future studies in TGF-β-dependent mechanisms in obesity-associated inflammatory airway diseases will advance our understanding of obesity-induced asthma and help find novel therapeutic targets for prevention and treatment.
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Affiliation(s)
- Joanna Woo
- Rutgers Institute for Translational Medicine & Science, The State University of New Jersey, 89 French Street, Rutgers, 160 Frelinghuysen Road, Piscataway, NJ08854, United States
- Ernest Mario School of Pharmacy, The State University of New Jersey, 89 French Street, Rutgers, 160 Frelinghuysen Road, Piscataway, NJ08854, United States
| | - Cynthia Koziol-White
- Rutgers Institute for Translational Medicine & Science, The State University of New Jersey, 89 French Street, Rutgers, 160 Frelinghuysen Road, Piscataway, NJ08854, United States
- Robert Wood Johnson Medical School, The State University of New Jersey, 89 French Street, Rutgers, 160 Frelinghuysen Road, Piscataway, NJ08854, United States
| | - Reynold Panettieri
- Rutgers Institute for Translational Medicine & Science, The State University of New Jersey, 89 French Street, Rutgers, 160 Frelinghuysen Road, Piscataway, NJ08854, United States
- Robert Wood Johnson Medical School, The State University of New Jersey, 89 French Street, Rutgers, 160 Frelinghuysen Road, Piscataway, NJ08854, United States
- Ernest Mario School of Pharmacy, The State University of New Jersey, 89 French Street, Rutgers, 160 Frelinghuysen Road, Piscataway, NJ08854, United States
| | - Joseph Jude
- Rutgers Institute for Translational Medicine & Science, The State University of New Jersey, 89 French Street, Rutgers, 160 Frelinghuysen Road, Piscataway, NJ08854, United States
- Robert Wood Johnson Medical School, The State University of New Jersey, 89 French Street, Rutgers, 160 Frelinghuysen Road, Piscataway, NJ08854, United States
- Ernest Mario School of Pharmacy, The State University of New Jersey, 89 French Street, Rutgers, 160 Frelinghuysen Road, Piscataway, NJ08854, United States
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Kim MJ, O'Connor MB. Drosophila Activin signaling promotes muscle growth through InR/TORC1-dependent and -independent processes. Development 2021; 148:dev190868. [PMID: 33234715 PMCID: PMC7823159 DOI: 10.1242/dev.190868] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 11/16/2020] [Indexed: 12/25/2022]
Abstract
The Myostatin/Activin branch of the TGF-β superfamily acts as a negative regulator of vertebrate skeletal muscle size, in part, through downregulation of insulin/insulin-like growth factor 1 (IGF-1) signaling. Surprisingly, recent studies in Drosophila indicate that motoneuron-derived Activin signaling acts as a positive regulator of muscle size. Here we demonstrate that Drosophila Activin signaling promotes the growth of muscle cells along all three axes: width, thickness and length. Activin signaling positively regulates the insulin receptor (InR)/TORC1 pathway and the level of Myosin heavy chain (Mhc), an essential sarcomeric protein, via increased Pdk1 and Akt1 expression. Enhancing InR/TORC1 signaling in the muscle of Activin pathway mutants restores Mhc levels close to those of the wild type, but only increases muscle width. In contrast, hyperactivation of the Activin pathway in muscles increases overall larval body and muscle fiber length, even when Mhc levels are lowered by suppression of TORC1. Together, these results indicate that the Drosophila Activin pathway regulates larval muscle geometry and body size via promoting InR/TORC1-dependent Mhc production and the differential assembly of sarcomeric components into either pre-existing or new sarcomeric units depending on the balance of InR/TORC1 and Activin signals.
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Affiliation(s)
- Myung-Jun Kim
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
| | - Michael B O'Connor
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
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McIlvenna LC, Patten RK, McAinch AJ, Rodgers RJ, Stepto NK, Moreno-Asso A. Transforming Growth Factor Beta 1 Alters Glucose Uptake but Not Insulin Signalling in Human Primary Myotubes From Women With and Without Polycystic Ovary Syndrome. Front Endocrinol (Lausanne) 2021; 12:732338. [PMID: 34707569 PMCID: PMC8544291 DOI: 10.3389/fendo.2021.732338] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 09/22/2021] [Indexed: 12/24/2022] Open
Abstract
Women with polycystic ovary syndrome (PCOS), commonly have profound skeletal muscle insulin resistance which can worsen other clinical features. The heterogeneity of the condition has made it challenging to identify the precise mechanisms that cause this insulin resistance. A possible explanation for the underlying insulin resistance may be the dysregulation of Transforming Growth Factor-beta (TGFβ) signalling. TGFβ signalling contributes to the remodelling of reproductive and hepatic tissues in women with PCOS. Given the systemic nature of TGFβ signalling and its role in skeletal muscle homeostasis, it may be possible that these adverse effects extend to other peripheral tissues. We aimed to determine if TGFβ1 could negatively regulate glucose uptake and insulin signalling in skeletal muscle of women with PCOS. We show that both myotubes from women with PCOS and healthy women displayed an increase in glucose uptake, independent of changes in insulin signalling, following short term (16 hr) TGFβ1 treatment. This increase occurred despite pro-fibrotic signalling increasing via SMAD3 and connective tissue growth factor in both groups following treatment with TGFβ1. Collectively, our findings show that short-term treatment with TGFβ1 does not appear to influence insulin signalling or promote insulin resistance in myotubes. These findings suggest that aberrant TGFβ signalling is unlikely to directly contribute to skeletal muscle insulin resistance in women with PCOS in the short term but does not rule out indirect or longer-term effects.
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Affiliation(s)
- Luke C. McIlvenna
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Rhiannon K. Patten
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Andrew J. McAinch
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, Melbourne, VIC, Australia
| | - Raymond J. Rodgers
- Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Nigel K. Stepto
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, Melbourne, VIC, Australia
| | - Alba Moreno-Asso
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, Melbourne, VIC, Australia
- *Correspondence: Alba Moreno-Asso,
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42
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Sheng J, Wang L, Tang PMK, Wang HL, Li JC, Xu BH, Xue VW, Tan RZ, Jin N, Chan TF, Huang XR, Ma RCW, Lan HY. Smad3 deficiency promotes beta cell proliferation and function in db/db mice via restoring Pax6 expression. Theranostics 2021; 11:2845-2859. [PMID: 33456576 PMCID: PMC7806493 DOI: 10.7150/thno.51857] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 12/11/2020] [Indexed: 12/18/2022] Open
Abstract
Rationale: Transforming Growth Factor-beta (TGF-β) /Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases, but its role in beta cell function and type 2 diabetes is unknown. Methods: The role of Smad3 in beta cell function under type 2 diabetes condition was investigated by genetically deleting Smad3 from db/db mice. Phenotypic changes of pancreatic islets and beta cell function were compared between Smad3 knockout db/db (Smad3KO-db/db) mice and Smad3 wild-type db/db (Smad3WT-db/db) mice, and other littermate controls. Islet-specific RNA-sequencing was performed to identify Smad3-dependent differentially expressed genes associated with type 2 diabetes. In vitro beta cell proliferation assay and insulin secretion assay were carried out to validate the mechanism by which Smad3 regulates beta cell proliferation and function. Results: The results showed that Smad3 deficiency completely protected against diabetes-associated beta cell loss and dysfunction in db/db mice. By islet-specific RNA-sequencing, we identified 8160 Smad3-dependent differentially expressed genes associated with type 2 diabetes, where Smad3 deficiency markedly prevented the down-regulation of those genes. Mechanistically, Smad3 deficiency preserved the expression of beta cell development mediator Pax6 in islet, thereby enhancing beta cell proliferation and function in db/db mice in vivo and in Min6 cells in vitro. Conclusions: Taken together, we discovered a pathogenic role of Smad3 in beta cell loss and dysfunction via targeting the protective Pax6. Thus, Smad3 may represent as a novel therapeutic target for type 2 diabetes prevention and treatment.
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Andrade S, Morais T, Sandovici I, Seabra AL, Constância M, Monteiro MP. Adipose Tissue Epigenetic Profile in Obesity-Related Dysglycemia - A Systematic Review. Front Endocrinol (Lausanne) 2021; 12:681649. [PMID: 34290669 PMCID: PMC8288106 DOI: 10.3389/fendo.2021.681649] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/26/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Obesity is a major risk factor for dysglycemic disorders, including type 2 diabetes (T2D). However, there is wide phenotypic variation in metabolic profiles. Tissue-specific epigenetic modifications could be partially accountable for the observed phenotypic variability. SCOPE The aim of this systematic review was to summarize the available data on epigenetic signatures in human adipose tissue (AT) that characterize overweight or obesity-related insulin resistance (IR) and dysglycemia states and to identify potential underlying mechanisms through the use of unbiased bioinformatics approaches. METHODS Original data published in the last decade concerning the comparison of epigenetic marks in human AT of individuals with metabolically unhealthy overweight/obesity (MUHO) versus normal weight individuals or individuals with metabolically healthy overweight/obesity (MHO) was assessed. Furthermore, association of these epigenetic marks with IR/dysglycemic traits, including T2D, was compiled. RESULTS We catalogued more than two thousand differentially methylated regions (DMRs; above the cut-off of 5%) in the AT of individuals with MUHO compared to individuals with MHO. These DNA methylation changes were less likely to occur around the promoter regions and were enriched at loci implicated in intracellular signaling (signal transduction mediated by small GTPases, ERK1/2 signaling and intracellular trafficking). We also identified a network of seven transcription factors that may play an important role in targeting DNA methylation changes to specific genes in the AT of subjects with MUHO, contributing to the pathogeny of obesity-related IR/T2D. Furthermore, we found differentially methylated CpG sites at 8 genes that were present in AT and whole blood, suggesting that DMRs in whole blood could be potentially used as accessible biomarkers of MUHO. CONCLUSIONS The overall evidence linking epigenetic alterations in key tissues such AT to metabolic complications in human obesity is still very limited, highlighting the need for further studies, particularly those focusing on epigenetic marks other than DNA methylation. Our initial analysis suggests that DNA methylation patterns can potentially discriminate between MUHO from MHO and provide new clues into why some people with obesity are less susceptible to dysglycemia. Identifying AT-specific epigenetic targets could also lead to novel approaches to modify the progression of individuals with obesity towards metabolic disease. SYSTEMATIC REVIEW REGISTRATION PROSPERO, identifier CRD42021227237.
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Affiliation(s)
- Sara Andrade
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal
- Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Tiago Morais
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal
- Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Ionel Sandovici
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, United Kingdom
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Alexandre L. Seabra
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal
- Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Miguel Constância
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, United Kingdom
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
- National Institute of Health Research, Cambridge Biomedical Research Centre, Cambridge, United Kingdom
| | - Mariana P. Monteiro
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal
- Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
- *Correspondence: Mariana P. Monteiro,
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Alshargabi R, Shinjo T, Iwashita M, Yamashita A, Sano T, Nishimura Y, Hayashi M, Zeze T, Fukuda T, Sanui T, Nishimura F. SPOCK1 induces adipose tissue maturation: New insights into the function of SPOCK1 in metabolism. Biochem Biophys Res Commun 2020; 533:1076-1082. [PMID: 33012508 DOI: 10.1016/j.bbrc.2020.09.129] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 09/26/2020] [Indexed: 11/24/2022]
Abstract
SPOCK1 is a calcium-binding matricellular proteoglycan that has been extensively studied in several cancer cells. Previously, we generated a mouse line overexpressing SPOCK1 (Spock1-Tg mouse) and showed that SPOCK1 might play an important role in drug-induced gingival overgrowth, indicating that it possesses physiological functions in non-cancer diseases as well. Although SPOCK1 was reported to be secreted from human adipocytes, its role in adipocyte physiology has not been addressed yet. In this study, SPOCK1 protein expression was confirmed in pancreas, adipose tissues, spleen, and liver of normal diet (ND)-fed mice. Interestingly, SPOCK1 was up-regulated in the pancreas and adipose tissues of the high-fat diet (HFD)-fed mice. Spock1-Tg mice fed with ND showed increased maturation in epididymal and inguinal adipose tissues. In addition, Spock1 overexpression strongly decreased expression of UCP-1 in adipose tissues, suggesting that SPOCK1 might regulate thermogenic function through suppression of UCP-1 expression. Finally, exogenous SPOCK1 treatment directly accelerated the differentiation of 3T3-L1 adipocytes, accompanied by the up-regulation of adipocyte differentiation-related gene expression. In conclusion, we demonstrated for the first time that SPOCK1 induced adipocyte differentiation via the up-regulation of adipogenesis-related genes.
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Affiliation(s)
- Rehab Alshargabi
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takanori Shinjo
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Misaki Iwashita
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Akiko Yamashita
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tomomi Sano
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yuki Nishimura
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masato Hayashi
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tatsuro Zeze
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takao Fukuda
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Terukazu Sanui
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Fusanori Nishimura
- Section of Periodontology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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Wade H, Pan K, Su Q. CREBH: A Complex Array of Regulatory Mechanisms in Nutritional Signaling, Metabolic Inflammation, and Metabolic Disease. Mol Nutr Food Res 2020; 65:e2000771. [DOI: 10.1002/mnfr.202000771] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Henry Wade
- Institute for Global Food Security School of Biological Sciences Queen's University Belfast Belfast BT9 5DL UK
| | - Kaichao Pan
- Institute for Global Food Security School of Biological Sciences Queen's University Belfast Belfast BT9 5DL UK
| | - Qiaozhu Su
- Institute for Global Food Security School of Biological Sciences Queen's University Belfast Belfast BT9 5DL UK
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Wang DC, Yan TT, Chen B, Liu F, Liu XP, Xie YM. SIS3, a good candidate for the reverse of type 2 diabetes mellitus in mice. Fundam Clin Pharmacol 2020; 35:389-396. [PMID: 33022778 DOI: 10.1111/fcp.12611] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 07/17/2020] [Accepted: 09/30/2020] [Indexed: 02/05/2023]
Abstract
TGF-β signaling plays an extremely important role in the occurrence and development of type 2 diabetes mellitus (T2DM), and the blockade of TGF-β/Smad3 pathway protests against the high-fat diet-induced obesity and diabetes. As a specific small molecule inhibitor of Smad3 protein, the biological activities of compound SIS3 were evaluated by high-fat diet-induced T2DM model mice. In vivo results indicated that SIS3 can not only significantly reduce the body weight, fat mass, and fasting blood glucose in high-fat diet-induced T2DM model mice, but also improve insulin sensitivity and oral glucose tolerance of high-fat diet-induced T2DM model mice after the injection of SIS3 with 5 mg/kg for 45 days.
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Affiliation(s)
- Dao-Cai Wang
- Hubei Key Laboratory of Biologic Resources Protection and Utilization, College of Biological Science and Technology, Hubei Minzu University, Enshi, 445000, China
| | - Ting-Ting Yan
- State Key Laboratory of Biotherapy and Cancer Center, Department of Thyroid Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Bin Chen
- State Key Laboratory of Biotherapy and Cancer Center, Department of Thyroid Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Feng Liu
- State Key Laboratory of Biotherapy and Cancer Center, Department of Thyroid Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Xiao-Peng Liu
- Hubei Key Laboratory of Biologic Resources Protection and Utilization, College of Biological Science and Technology, Hubei Minzu University, Enshi, 445000, China
| | - Yong-Mei Xie
- State Key Laboratory of Biotherapy and Cancer Center, Department of Thyroid Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
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Anderson AK, Lambert JM, Montefusco DJ, Tran BN, Roddy P, Holland WL, Cowart LA. Depletion of adipocyte sphingosine kinase 1 leads to cell hypertrophy, impaired lipolysis, and nonalcoholic fatty liver disease. J Lipid Res 2020; 61:1328-1340. [PMID: 32690594 PMCID: PMC7529052 DOI: 10.1194/jlr.ra120000875] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Sphingolipids have become established participants in the pathogenesis of obesity and its associated maladies. Sphingosine kinase 1 (SPHK1), which generates S1P, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 KO mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and NAFLD, suggesting that SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction has gained recognition as a central instigator of obesity-induced metabolic disease, we hypothesized that SPHK1 intrinsic to adipocytes may contribute to HFD-induced metabolic pathology. To test this, we depleted Sphk1 from adipocytes in mice (SK1fatKO) and placed them on a HFD. In contrast to our initial hypothesis, SK1fatKO mice displayed greater weight gain on HFD and exacerbated impairment in glucose clearance. Pro-inflammatory cytokines and neutrophil content of adipose tissue were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of pro-inflammatory cytokines and collagen 1a1 were exacerbated in SK1fatKO mice on a HFD, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ cross-talk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.
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Affiliation(s)
- Andrea K Anderson
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
- Departments of Biochemistry and Molecular Biology Medical University of South Carolina, Charleston, SC, USA
| | - Johana M Lambert
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
- Departments of Biochemistry and Molecular Biology Medical University of South Carolina, Charleston, SC, USA
| | - David J Montefusco
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Bao Ngan Tran
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Patrick Roddy
- Department of Regenerative Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - William L Holland
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - L Ashley Cowart
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
- Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, USA
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48
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Roh HC, Kumari M, Taleb S, Tenen D, Jacobs C, Lyubetskaya A, Tsai LTY, Rosen ED. Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling. Mol Metab 2020; 42:101086. [PMID: 32992037 PMCID: PMC7559520 DOI: 10.1016/j.molmet.2020.101086] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/09/2020] [Accepted: 09/17/2020] [Indexed: 12/11/2022] Open
Abstract
Objective Obesity due to overnutrition causes adipose tissue dysfunction, which is a critical pathological step on the road to type 2 diabetes (T2D) and other metabolic disorders. In this study, we conducted an unbiased investigation into the fundamental molecular mechanisms by which adipocytes transition to an unhealthy state during obesity. Methods We used nuclear tagging and translating ribosome affinity purification (NuTRAP) reporter mice crossed with Adipoq-Cre mice to determine adipocyte-specific 1) transcriptional profiles (RNA-seq), 2) promoter and enhancer activity (H3K27ac ChIP-seq), 3) and PPARγ cistrome (ChIP-seq) profiles in mice fed chow or a high-fat diet (HFD) for 10 weeks. We also assessed the impact of the PPARγ agonist rosiglitazone (Rosi) on gene expression and cellular state of adipocytes from the HFD-fed mice. We integrated these data to determine the transcription factors underlying adipocyte responses to HFD and conducted functional studies using shRNA-mediated loss-of-function approaches in 3T3-L1 adipocytes. Results Adipocytes from the HFD-fed mice exhibited reduced expression of adipocyte markers and metabolic genes and enhanced expression of myofibroblast marker genes involved in cytoskeletal organization, accompanied by the formation of actin filament structures within the cell. PPARγ binding was globally reduced in adipocytes after HFD feeding, and Rosi restored the molecular and cellular phenotypes of adipocytes associated with HFD feeding. We identified the TGFβ1 effector protein SMAD to be enriched at HFD-induced promoters and enhancers and associated with myofibroblast signature genes. TGFβ1 treatment of mature 3T3-L1 adipocytes induced gene expression and cellular changes similar to those seen after HFD in vivo, and knockdown of Smad3 blunted the effects of TGFβ1. Conclusions Our data demonstrate that adipocytes fail to maintain cellular identity after HFD feeding, acquiring characteristics of a myofibroblast-like cell type through reduced PPARγ activity and elevated TGFβ-SMAD signaling. This cellular identity crisis may be a fundamental mechanism that drives functional decline of adipose tissues during obesity.
Adipocytes after HFD intake exhibit defects in cellular identity maintenance. Adipocytes develop actin filament networks in obesity. Altered PPARγ activity mediates defective adipocyte identity phenotypes. TGFβ-SMAD pathways promote HFD-induced aberrant phenotype of adipocytes.
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Affiliation(s)
- Hyun Cheol Roh
- Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
| | - Manju Kumari
- Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA
| | - Solaema Taleb
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Danielle Tenen
- Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USA
| | - Christopher Jacobs
- Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USA
| | - Anna Lyubetskaya
- Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USA
| | - Linus T-Y Tsai
- Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USA
| | - Evan D Rosen
- Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USA.
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Cubillos-Zapata C, Martínez-García MÁ, Díaz-García E, Jaureguizar A, Campos-Rodríguez F, Sánchez-de-la-Torre M, Nagore E, Martorell-Calatayud A, Blasco LH, Pastor E, Abad-Capa J, Montserrat JM, Cabriada-Nuño V, Cano-Pumarega I, Corral-Peñafiel J, Arias E, Mediano O, Somoza-González M, Dalmau-Arias J, Almendros I, Farré R, López-Collazo E, Gozal D, García-Río F. Obesity attenuates the effect of sleep apnea on active TGF-ß1 levels and tumor aggressiveness in patients with melanoma. Sci Rep 2020; 10:15528. [PMID: 32968152 PMCID: PMC7511355 DOI: 10.1038/s41598-020-72481-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 07/09/2020] [Indexed: 12/14/2022] Open
Abstract
Active transforming growth factor-β1 (TGF-β1), a cytokine partially regulated by hypoxia and obesity, has been related with poor prognosis in several tumors. We determine whether obstructive sleep apnea (OSA) increases serum levels of active TGF-β1 in patients with cutaneous melanoma (CM), assess their relationship with melanoma aggressiveness and analyze the factors related to TGF-β1 levels in obese and non-obese OSA patients. In a multicenter observational study, 290 patients with CM were underwent sleep studies. TGF-β1 was increased in moderate-severe OSA patients vs. non-OSA or mild OSA patients with CM. In OSA patients, TGF-β1 levels correlated with mitotic index, Breslow index and melanoma growth rate, and were increased in presence of ulceration or higher Clark levels. In CM patients, OSA was associated with higher TGF-β1 levels and greater melanoma aggressiveness only in non-obese subjects. An in vitro model showed that IH-induced increases of TGF-β1 expression in melanoma cells is attenuated in the presence of high leptin levels. In conclusion, TGF-β1 levels are associated with melanoma aggressiveness in CM patients and increased in moderate-severe OSA. Moreover, in non-obese patients with OSA, TGF-β1 levels correlate with OSA severity and leptin levels, whereas only associate with leptin levels in obese OSA patients.
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Affiliation(s)
- Carolina Cubillos-Zapata
- Grupo de Enfermedades Respiratorias, Servicio de Neumología, Hospital Universitario La Paz-IdiPAZ, Paseo de La Castellana 261, 28046, Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Miguel Ángel Martínez-García
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Respiratory Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Elena Díaz-García
- Grupo de Enfermedades Respiratorias, Servicio de Neumología, Hospital Universitario La Paz-IdiPAZ, Paseo de La Castellana 261, 28046, Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Ana Jaureguizar
- Grupo de Enfermedades Respiratorias, Servicio de Neumología, Hospital Universitario La Paz-IdiPAZ, Paseo de La Castellana 261, 28046, Madrid, Spain
| | - Francisco Campos-Rodríguez
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Respiratory Department, Hospital Universitario de Valme, IBIS, Seville, Spain
| | - Manuel Sánchez-de-la-Torre
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Group of Precision Medicine in Chronic Diseases, Hospital Universitari Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
| | - Eduardo Nagore
- Dermatology Department, Instituto Valenciano de Oncología, Valencia, Spain
| | | | - Luis Hernández Blasco
- Respiratory Department, ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
- Departamento Medicina Clinica, Universidad Miguel Hernandez, Elche, Spain
| | - Esther Pastor
- Respiratory Department, Hospital San Juan de Alicante, Alicante, Spain
| | - Jorge Abad-Capa
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Respiratory Department, Centro de Investigacion Biomedica, Hospital Germans Trias i Pujol, Madrid, Spain
| | - Josep María Montserrat
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Respiratory Department, Hospital Clinic- IDIBAPS, Barcelona, Spain
| | | | | | - Jaime Corral-Peñafiel
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Respiratory Department, Hospital Universitario S. Pedro Alcántara, Cáceres, Spain
| | - Eva Arias
- Respiratory Department, Hospital 12 de Octubre, Madrid, Spain
| | - Olga Mediano
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Respiratory Department, Hospital Universitario de Guadalajara, Guadalajara, Spain
| | | | - Joan Dalmau-Arias
- Dermatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Isaac Almendros
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Unitat de Biofísica I Bioenginyeria, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ramón Farré
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Unitat de Biofísica I Bioenginyeria, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Eduardo López-Collazo
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain
- TumorImmunology Laboratory IdiPAZ, Madrid, Spain
- Innate Immune Response Group, IdiPAZ, Madrid, Spain
| | - David Gozal
- Department of Child Health, University of Missouri School of Medicine, Columbia, MO, USA
| | - Francisco García-Río
- Grupo de Enfermedades Respiratorias, Servicio de Neumología, Hospital Universitario La Paz-IdiPAZ, Paseo de La Castellana 261, 28046, Madrid, Spain.
- Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain.
- Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
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Sambon M, Gorlova A, Demelenne A, Alhama-Riba J, Coumans B, Lakaye B, Wins P, Fillet M, Anthony DC, Strekalova T, Bettendorff L. Dibenzoylthiamine Has Powerful Antioxidant and Anti-Inflammatory Properties in Cultured Cells and in Mouse Models of Stress and Neurodegeneration. Biomedicines 2020; 8:biomedicines8090361. [PMID: 32962139 PMCID: PMC7555733 DOI: 10.3390/biomedicines8090361] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/03/2020] [Accepted: 09/16/2020] [Indexed: 12/14/2022] Open
Abstract
Thiamine precursors, the most studied being benfotiamine (BFT), have protective effects in mouse models of neurodegenerative diseases. BFT decreased oxidative stress and inflammation, two major characteristics of neurodegenerative diseases, in a neuroblastoma cell line (Neuro2a) and an immortalized brain microglial cell line (BV2). Here, we tested the potential antioxidant and anti-inflammatory effects of the hitherto unexplored derivative O,S-dibenzoylthiamine (DBT) in these two cell lines. We show that DBT protects Neuro2a cells against paraquat (PQ) toxicity by counteracting oxidative stress at low concentrations and increases the synthesis of reduced glutathione and NADPH in a Nrf2-independent manner. In BV2 cells activated by lipopolysaccharides (LPS), DBT significantly decreased inflammation by suppressing translocation of NF-κB to the nucleus. Our results also demonstrate the superiority of DBT over thiamine and other thiamine precursors, including BFT, in all of the in vitro models. Finally, we show that the chronic administration of DBT arrested motor dysfunction in FUS transgenic mice, a model of amyotrophic lateral sclerosis, and it reduced depressive-like behavior in a mouse model of ultrasound-induced stress in which it normalized oxidative stress marker levels in the brain. Together, our data suggest that DBT may have therapeutic potential for brain pathology associated with oxidative stress and inflammation by novel, coenzyme-independent mechanisms.
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Affiliation(s)
- Margaux Sambon
- Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium; (M.S.); (J.A.-R.); (P.W.)
| | - Anna Gorlova
- Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands; (A.G.); (T.S.)
- Institute of Molecular Medicine Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
| | - Alice Demelenne
- Laboratory for the Analysis of Medicines, CIRM, Department of Pharmacy, University of Liège, 4000 Liège, Belgium; (A.D.); (M.F.)
| | - Judit Alhama-Riba
- Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium; (M.S.); (J.A.-R.); (P.W.)
- Faculty of Sciences, University of Girona, 17004 Girona, Spain
| | - Bernard Coumans
- Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cell, University of Liège, 4000 Liège, Belgium; (B.C.); (B.L.)
| | - Bernard Lakaye
- Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cell, University of Liège, 4000 Liège, Belgium; (B.C.); (B.L.)
| | - Pierre Wins
- Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium; (M.S.); (J.A.-R.); (P.W.)
| | - Marianne Fillet
- Laboratory for the Analysis of Medicines, CIRM, Department of Pharmacy, University of Liège, 4000 Liège, Belgium; (A.D.); (M.F.)
| | - Daniel C. Anthony
- Institute of Molecular Medicine Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK
| | - Tatyana Strekalova
- Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands; (A.G.); (T.S.)
- Institute of Molecular Medicine Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
| | - Lucien Bettendorff
- Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium; (M.S.); (J.A.-R.); (P.W.)
- Correspondence: ; Tel.: +32-4-366-5967
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