|
1
|
Liu J, Jiang Y, Liu T, Chen C, Chui L, Cui A, Zhang X, Wang X, Wang Y, Yang C, Zhang Y, Wu T, Yang S, Huang J, Tao C, Zhao J, Wang Y. Single-nucleus RNA sequencing defines adipose tissue subpopulations that contribute to Tibetan pig cold adaptation. BMC Biol 2025; 23:107. [PMID: 40275312 PMCID: PMC12023645 DOI: 10.1186/s12915-025-02211-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 04/09/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Thermogenic beige adipocyte displays a remarkable ability in mammals to adapt to cold environments, but the underlying cellular mechanisms remain unclear, especially in pigs that lack functional UCP1. RESULTS Multilocular beige adipocytes were observed in both Tibetan pigs (cold-tolerant) and Bama pigs (cold-sensitive) after short-term cold exposure (4 ℃ for 3 days). Through single-nucleus RNA sequencing of adipose tissues, including subcutaneous inguinal adipose tissues (IAT) and perirenal adipose tissues (PAT), from both pig breeds at room temperature and cold treatment conditions, we discovered two cell subpopulations specific to Tibetan pigs, PDGFRα+EBF2High in IAT and ADIPOQ+HIF1AHigh in both depots. PDGFRα+EBF2High cells were characterized as potential beige precursors, while ADIPOQ+HIF1AHigh cells were found to express highly thermogenic-related genes. Despite the decrease of the lipogenic subpopulation and the increase of the lipolytic and the thermogenic subpopulations observed in both pig breeds upon cold treatment, Tibetan pigs exhibited stronger cellular and molecular responses compared to Bama pigs. Remarkably, cold-induced de novo beige adipogenesis and white adipocyte browning, likely occurred in Tibetan pigs, while Bama pigs relied more heavily on white browning. Moreover, BMP7, which was highly expressed in the PDGFRα+EBF2High subpopulation, positively regulates porcine beige thermogenic capacity. CONCLUSIONS Our data offers a comprehensive and unprecedented perspective on the heterogeneity and plasticity of adipose tissues of pigs and broadens the understanding of beige fat biology in mammals.
Collapse
Affiliation(s)
- Jiali Liu
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China
| | - Yao Jiang
- National Animal Husbandry Service, Beijing, 100125, China
| | - Tianxia Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Lnstitute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Chuanhe Chen
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China
| | - Linya Chui
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China
- College of Life Sciences, Qingdao Agricultural University, Qingdao, 266109, China
| | - Along Cui
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Lnstitute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Xueping Zhang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Xiao Wang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China
| | - Yu Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Lnstitute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Chunhuai Yang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China
| | - Ying Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Lnstitute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Tianwen Wu
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China
| | - Shulin Yang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China
| | - Jiaojiao Huang
- College of Life Sciences, Qingdao Agricultural University, Qingdao, 266109, China
| | - Cong Tao
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China.
| | - Jianguo Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Lnstitute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- Sanya Institute, Hainan Academy of Agricultural Sciences, Sanya, 572025, China.
| | - Yanfang Wang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China.
- Sanya Institute, Hainan Academy of Agricultural Sciences, Sanya, 572025, China.
| |
Collapse
|
|
2
|
Pahlavani M, Pham K, Kalupahana NS, Morovati A, Ramalingam L, Abidi H, Kiridana V, Moustaid-Moussa N. Thermogenic adipose tissues: Promising therapeutic targets for metabolic diseases. J Nutr Biochem 2025; 137:109832. [PMID: 39653156 DOI: 10.1016/j.jnutbio.2024.109832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 11/30/2024] [Accepted: 12/04/2024] [Indexed: 01/03/2025]
Abstract
The ongoing increase in the prevalence of obesity and its comorbidities such as cardiovascular disease, type 2 diabetes (T2D) and dyslipidemia warrants discovery of novel therapeutic options for these metabolic diseases. Obesity is characterized by white adipose tissue expansion due to chronic positive energy balance as a result of excessive energy intake and/or reduced energy expenditure. Despite various efforts to prevent or reduce obesity including lifestyle and behavioral interventions, surgical weight reduction approaches and pharmacological methods, there has been limited success in significantly reducing obesity prevalence. Recent research has shown that thermogenic adipocyte (brown and beige) activation or formation, respectively, could potentially act as a therapeutic strategy to ameliorate obesity and its related disorders. This can be achieved through the ability of these thermogenic cells to enhance energy expenditure and regulate circulating levels of glucose and lipids. Thus, unraveling the molecular mechanisms behind the formation and activation of brown and beige adipocytes holds the potential for probable therapeutic paths to combat obesity. In this review, we provide a comprehensive update on the development and regulation of different adipose tissue types. We also emphasize recent interventions in harnessing therapeutic potential of thermogenic adipocytes by bioactive compounds and new pharmacological anti-obesity agents.
Collapse
Affiliation(s)
- Mandana Pahlavani
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA; Obesity Research Institute, Texas Tech University, Lubbock, Texas, USA; Department of Nutrition and Food Sciences, Texas Woman's University, Dallas, Texas, USA
| | - Kenneth Pham
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA
| | - Nishan Sudheera Kalupahana
- Department of Nutrition and Health, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE
| | - Ashti Morovati
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA; Obesity Research Institute, Texas Tech University, Lubbock, Texas, USA
| | - Latha Ramalingam
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA; Obesity Research Institute, Texas Tech University, Lubbock, Texas, USA; Department of Nutrition and Food Studies, Syracuse University, Syracuse, New York, USA
| | - Hussain Abidi
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA
| | - Vasana Kiridana
- Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA; Obesity Research Institute, Texas Tech University, Lubbock, Texas, USA; Institute for One Health Innovation, Texas Tech University and Texas Tech Health Sciences Center, Lubbock, Texas, USA.
| |
Collapse
|
|
3
|
Wang Y, Fu J, He W, Gao Y, Du J, Xu J, Guo L, Liu Y. Bone marrow mesenchymal stem cells ameliorate diet-induced obesity by activating thermogenesis and alleviating inflammation in adipose tissue. Biochem Biophys Res Commun 2025; 747:151172. [PMID: 39793396 DOI: 10.1016/j.bbrc.2024.151172] [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: 12/05/2024] [Revised: 12/07/2024] [Accepted: 12/10/2024] [Indexed: 01/13/2025]
Abstract
Obesity and its related metabolic disorders seriously threaten our health and significantly reduce our life expectancy. The aim of the present study was to explore the effects of bone marrow mesenchymal stem cells (BMSCs) on high-fat diet (HFD)-induced obesity mice. The results demonstrated that BMSCs significantly reduced body weight, improved glucose tolerance and insulin sensitivity in obese mice. Further analysis showed that BMSCs could promote brown adipose tissue (BAT) activity and white adipose tissue (WAT) browning by increasing the expression of mitochondrial uncouple protein 1 (UCP1). Additionally, BMSCs markedly increase mitochondrial biogenesis, activate oxidative phosphorylation (OXPHOS) in adipose tissue, further contributing to energy metabolism regulation. Moreover, BMSCs were effective in inhibiting macrophage-related inflammation in adipose tissue, thereby mitigating obesity-associated inflammatory responses. Overall, our results lay the foundation for research on the potential of BMSCs as a promising strategy in alleviating obesity and related metabolic diseases.
Collapse
Affiliation(s)
- Yanxue Wang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, PR China.
| | - Jingfei Fu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, PR China.
| | - Wanghong He
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, PR China.
| | - Yike Gao
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, PR China.
| | - Juan Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, PR China.
| | - Junji Xu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, PR China.
| | - Lijia Guo
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, PR China; Department of Orthodontics (WangFuJing Campus), School of Stomatology, Capital Medical University, Beijing, PR China.
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, PR China.
| |
Collapse
|
|
4
|
Korobkina ED, Calejman CM, Haley JA, Kelly ME, Li H, Gaughan M, Chen Q, Pepper HL, Ahmad H, Boucher A, Fluharty SM, Lin TY, Lotun A, Peura J, Trefely S, Green CR, Vo P, Semenkovich CF, Pitarresi JR, Spinelli JB, Aydemir O, Metallo CM, Lynes MD, Jang C, Snyder NW, Wellen KE, Guertin DA. Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress. Nat Metab 2024; 6:2187-2202. [PMID: 39402290 PMCID: PMC11841677 DOI: 10.1038/s42255-024-01143-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 09/16/2024] [Indexed: 11/28/2024]
Abstract
Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT.
Collapse
Affiliation(s)
- Ekaterina D Korobkina
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Camila Martinez Calejman
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - John A Haley
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Miranda E Kelly
- Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
| | - Huawei Li
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Maria Gaughan
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Qingbo Chen
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Hannah L Pepper
- Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Hafsah Ahmad
- Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Alexander Boucher
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Shelagh M Fluharty
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Te-Yueh Lin
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Anoushka Lotun
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jessica Peura
- Division of Hematology-Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Sophie Trefely
- Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Courtney R Green
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | - Paula Vo
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Clay F Semenkovich
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Jason R Pitarresi
- Division of Hematology-Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jessica B Spinelli
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Ozkan Aydemir
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Christian M Metallo
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
- Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA
| | | | - Cholsoon Jang
- Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
| | - Nathaniel W Snyder
- Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Kathryn E Wellen
- Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - David A Guertin
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
| |
Collapse
|
|
5
|
Lietzke AC, Bealer E, Crumley K, King J, Stendahl AM, Zhu J, Pearson GL, Levi-D'Ancona E, Henry-Kanarek B, Reck EC, Arnipalli M, Sidarala V, Walker EM, Pennathur S, Madsen JGS, Shea LD, Soleimanpour SA. Limitations in mitochondrial programming restrain the differentiation and maturation of human stem cell-derived β cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.26.605318. [PMID: 39211191 PMCID: PMC11361182 DOI: 10.1101/2024.07.26.605318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation and maturation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we found that reductions in glucose- stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARIZ and PPARγ, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARIZ agonist, induced expression of mitochondrial targets, improved insulin secretion, and increased the formation and maturation of SC-β cells both in vitro and following transplantation. Thus, mitochondrial programming promotes the differentiation and maturation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.
Collapse
|
|
6
|
Foss-Freitas MC, Gilio D, da Rocha AM, Pais L, O'Leary MC, Rehm HL, Neidert A, Udler MS, Seale P, Oral EA, Chun TH. Early B-cell transcription factor-2 defect as a novel cause of lipodystrophy: disruption of the adipose tissue character and integrity. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.06.24.24309093. [PMID: 38978649 PMCID: PMC11230304 DOI: 10.1101/2024.06.24.24309093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
We report a novel cause of partial lipodystrophy associated with early B cell factor 2 (EBF2) nonsense variant (EBF2 8:26033143 C>A, c.493G>T, p.E165X) in a patient with an atypical form of partial lipodystrophy. The patient presented with progressive adipose tissue loss and metabolic deterioration at pre-pubertal age. In vitro and in vivo disease modeling demonstrates that the EBF2 variant impairs adipogenesis, causing excess accumulation of undifferentiated CD34+ cells, extracellular matrix proteins, and inflammatory myeloid cells in subcutaneous adipose tissues. Thus, this EBF2 p.E165X variant disrupts adipose tissue structure and function, leading to the development of partial lipodystrophy syndrome.
Collapse
Affiliation(s)
- Maria C Foss-Freitas
- Caswell Diabetes Institute and Metabolism, Endocrinology and Diabetes Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Donatella Gilio
- Caswell Diabetes Institute and Metabolism, Endocrinology and Diabetes Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Andre Monteiro da Rocha
- Frankel Cardiovascular Regeneration Core Laboratory, University of Michigan, Ann Arbor, Michigan
| | - Lynn Pais
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Melanie C O'Leary
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Heidi L Rehm
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Adam Neidert
- Caswell Diabetes Institute and Metabolism, Endocrinology and Diabetes Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Miriam S Udler
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Patrick Seale
- Institute for Diabetes, Obesity & Metabolism, Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | - Elif A Oral
- Caswell Diabetes Institute and Metabolism, Endocrinology and Diabetes Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Tae-Hwa Chun
- Caswell Diabetes Institute and Metabolism, Endocrinology and Diabetes Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
- Biointerfaces Institute, The University of Michigan, Ann Arbor, Michigan, USA
| |
Collapse
|
|
7
|
Dong M, An K, Mao L. High levels of uric acid inhibit BAT thermogenic capacity through regulation of AMPK. Am J Physiol Endocrinol Metab 2023; 325:E376-E389. [PMID: 37732807 PMCID: PMC10642990 DOI: 10.1152/ajpendo.00092.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 08/22/2023] [Accepted: 08/27/2023] [Indexed: 09/22/2023]
Abstract
Hyperuricemia (HUA) is strongly associated with the increasing prevalence of obesity, but the underlying mechanism remains elusive. Dysfunction of brown adipose tissue (BAT) could lead to obesity. However, studies on the role of HUA on BAT are lacking. Our retrospective clinical analysis showed that serum uric acid (UA) is significantly associated with BAT in humans. To investigate the role of UA in regulating BAT function, we used UA to treat primary brown adipocytes (BACs) in vitro and established HUA mice. In vitro results showed that HUA suppressed thermogenic gene expression and oxygen consumption rate. Accordingly, HUA mice exhibited lower energy expenditure and body temperature, with larger lipid droplets and lower thermogenic gene expression. These results demonstrate that HUA inhibits BAT thermogenic capacity in vitro and in vivo. To further elucidate the mechanism of UA on adipocytes, mRNA-sequencing analysis was performed and screened for "AMP-activated protein kinase (AMPK) signaling pathway" and "mitochondrial biogenesis." Further tests in vivo and in vitro showed that the phosphorylation of AMPK was suppressed by HUA. Activation of AMPK alleviated the inhibition of AMPK phosphorylation by HUA and increased mitochondrial biogenesis, subsequently restoring the impaired BAT thermogenic capacity in vitro and vivo. Thus, we confirmed that HUA suppresses mitochondrial biogenesis by regulating AMPK, thereby inhibiting BAT thermogenic capacity. Taken together, our study identifies UA as a novel regulator of BAT thermogenic capacity, providing a new strategy to combat obesity.NEW & NOTEWORTHY To investigate the effect and mechanism of UA on BAT thermogenic capacity, we established HUA models in vitro and in vivo, and performed RNA sequencing analysis. Our results revealed that HUA suppresses mitochondrial biogenesis by regulating AMPK, thereby inhibiting BAT thermogenic capacity. Taken together, our study identifies UA as a novel regulator of BAT thermogenic capacity, providing a new strategy to combat obesity.
Collapse
Affiliation(s)
- Meijuan Dong
- Department of Endocrinology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Kun An
- Department of Neurology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Li Mao
- Department of Endocrinology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, China
| |
Collapse
|
|
8
|
Engelhard CA, Khani S, Derdak S, Bilban M, Kornfeld JW. Nanopore sequencing unveils the complexity of the cold-activated murine brown adipose tissue transcriptome. iScience 2023; 26:107190. [PMID: 37564700 PMCID: PMC10410515 DOI: 10.1016/j.isci.2023.107190] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/28/2023] [Accepted: 06/16/2023] [Indexed: 08/12/2023] Open
Abstract
Alternative transcription increases transcriptome complexity by expression of multiple transcripts per gene. Annotation and quantification of transcripts using short-read sequencing is non-trivial. Long-read sequencing aims at overcoming these problems by sequencing full-length transcripts. Activation of brown adipose tissue (BAT) thermogenesis involves major transcriptomic remodeling and positively affects metabolism via increased energy expenditure. We benchmark Oxford Nanopore Technology (ONT) long-read sequencing protocols to Illumina short-read sequencing assessing alignment characteristics, gene and transcript detection and quantification, differential gene and transcript expression, transcriptome reannotation, and differential transcript usage (DTU). We find ONT sequencing is superior to Illumina for transcriptome reassembly, reducing the risk of false-positive events by unambiguously mapping reads to transcripts. We identified novel isoforms of genes undergoing DTU in cold-activated BAT including Cars2, Adtrp, Acsl5, Scp2, Aldoa, and Pde4d, validated by real-time PCR. The reannotated murine BAT transcriptome established here provides a framework for future investigations into the regulation of BAT.
Collapse
Affiliation(s)
- Christoph Andreas Engelhard
- Department for Biochemistry and Molecular Biology (BMB), University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
| | - Sajjad Khani
- Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Sophia Derdak
- Core Facilities, Medical University of Vienna, Lazarettgasse 14, 1090 Vienna, Austria
| | - Martin Bilban
- Department of Laboratory Medicine & Core Facilities, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Jan-Wilhelm Kornfeld
- Department for Biochemistry and Molecular Biology (BMB), University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
| |
Collapse
|
|
9
|
Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
Collapse
Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
| |
Collapse
|
|
10
|
Zhang W, Kong L, Zhong Z, Lin L, Li J, Zheng G. Short chain fatty acids increase fat oxidation and promote browning through β3-adrenergic receptor/AMP-activated protein kinase α signaling pathway in 3T3-L1 adipocytes. J Funct Foods 2023. [DOI: 10.1016/j.jff.2023.105488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023] Open
|
|
11
|
Armani A, Feraco A, Camajani E, Gorini S, Lombardo M, Caprio M. Nutraceuticals in Brown Adipose Tissue Activation. Cells 2022; 11:cells11243996. [PMID: 36552762 PMCID: PMC9776638 DOI: 10.3390/cells11243996] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/03/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Obesity and its associated comorbidities have become pandemic, and challenge the global healthcare system. Lifestyle changes, nutritional interventions and phamaceuticals should be differently combined in a personalized strategy to tackle such a public health burden. Altered brown adipose tissue (BAT) function contributes to the pathophysiology of obesity and glucose metabolism dysfunctions. BAT thermogenic activity burns glucose and fatty acids to produce heat through uncoupled respiration, and can dissipate the excessive calorie intake, reduce glycemia and circulate fatty acids released from white adipose tissue. Thus, BAT activity is expected to contribute to whole body energy homeostasis and protect against obesity, diabetes and alterations in lipid profile. To date, pharmacological therapies aimed at activating brown fat have failed in clinical trials, due to cardiovascular side effects or scarce efficacy. On the other hand, several studies have identified plant-derived chemical compounds capable of stimulating BAT thermogenesis in animal models, suggesting the translational applications of dietary supplements to fight adipose tissue dysfunctions. This review describes several nutraceuticals with thermogenic properties and provides indications, at a molecular level, of the regulation of the adipocyte thermogenesis by the mentioned phytochemicals.
Collapse
Affiliation(s)
- Andrea Armani
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
- Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, 00166 Rome, Italy
- Correspondence:
| | - Alessandra Feraco
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
- Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, 00166 Rome, Italy
| | - Elisabetta Camajani
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Stefania Gorini
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
- Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, 00166 Rome, Italy
| | - Mauro Lombardo
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
| | - Massimiliano Caprio
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
- Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, 00166 Rome, Italy
| |
Collapse
|
|
12
|
Kong L, Zhang W, Liu S, Zhong Z, Zheng G. Quercetin, Engelitin and Caffeic Acid of Smilax china L. Polyphenols, Stimulate 3T3-L1 Adipocytes to Brown-like Adipocytes Via β3-AR/AMPK Signaling Pathway. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2022; 77:529-537. [PMID: 35986845 DOI: 10.1007/s11130-022-00996-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 06/15/2023]
Abstract
The aim of the present study was to investigate the browning effects mechanism of Smilax china L. polyphenols (SCLP) and its monomer. In this study, polyphenols (SCLP, engeletin, quercetin and caffeic acid) markedly suppressed lipid accumulation. Polyphenols significantly up-graded the expression of protein kinase A (PKA), adipose triglyceride lipase (ATGL), peroxisome proliferators-activated receptors alpha (PPARα), carnitine palmitoyl transferase (CPT) and acyl-CoA oxidase (ACO) to promote lipolysis and β-oxidation. Moreover, polyphenols greatly enhanced mitochondrial biogenesis in adipocytes, as demonstrated by the expression of Nrf1 and Tfam were up-regulated. Furthermore, polyphenols treatment greatly up-regulated the browning program in adipocytes by increased brown-specific genes and proteins uncoupling protein 1 (UCP-1), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and PR domain containing 16 (PRDM16), as well as beige-specific genes (Tmem26, Tbx1, CD137, Cited1), especially engeletin. Further research found that the brown-specific markers were decreased by antagonist treatment of AMPK or β3-AR, but polyphenols treatment reversed the effect of antagonists and improved the expression of UCP-1, PRDM16 and PGC-1α. In conclusion, these results indicated that polyphenols stimulate browning in adipocytes via activation of the β3-AR/AMPK signaling pathway, and SCLP and its monomer may be worth investigating to prevent obesity.
Collapse
Affiliation(s)
- Li Kong
- Jiangxi Key Laboratory of Natural Product and Functional Food, School of Food Science and Engineering, Jiangxi Agricultural University, 330045, Nanchang, Jiangxi Province, P.R. China
| | - Wenkai Zhang
- Jiangxi Key Laboratory of Natural Product and Functional Food, School of Food Science and Engineering, Jiangxi Agricultural University, 330045, Nanchang, Jiangxi Province, P.R. China
| | - Shanshan Liu
- Jiangxi Key Laboratory of Natural Product and Functional Food, School of Food Science and Engineering, Jiangxi Agricultural University, 330045, Nanchang, Jiangxi Province, P.R. China
| | - Zhen Zhong
- Jiangxi Key Laboratory of Natural Product and Functional Food, School of Food Science and Engineering, Jiangxi Agricultural University, 330045, Nanchang, Jiangxi Province, P.R. China
| | - Guodong Zheng
- Jiangxi Key Laboratory of Natural Product and Functional Food, School of Food Science and Engineering, Jiangxi Agricultural University, 330045, Nanchang, Jiangxi Province, P.R. China.
| |
Collapse
|
|
13
|
Sun L. WTAP: a new player in postnatal BAT development. LIFE METABOLISM 2022; 1:201-202. [PMID: 39872070 PMCID: PMC11749253 DOI: 10.1093/lifemeta/loac031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 10/31/2022] [Indexed: 01/29/2025]
Affiliation(s)
- Lei Sun
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore
| |
Collapse
|
|
14
|
Fujii M, Setoyama D, Gotoh K, Dozono Y, Yagi M, Ikeda M, Ide T, Uchiumi T, Kang D. TFAM expression in brown adipocytes confers obesity resistance by secreting extracellular vesicles that promote self-activation. iScience 2022; 25:104889. [PMID: 36046191 PMCID: PMC9421388 DOI: 10.1016/j.isci.2022.104889] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 06/03/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022] Open
Abstract
The occurrence of diet-induced obesity has been increasing worldwide and has become a major health concern. Mitochondria are densely distributed in brown adipose tissue and are involved in lipid consumption. Therefore, increasing energy expenditure through the activation of brown adipocytes may be a potential therapy for obesity. Our findings showed that mitochondrial transcription factor A (TFAM) homozygous transgenic (TgTg) mice had highly activated brown adipocytes and increased expression of oxidative phosphorylation, leading to resistance to obesity. Transplantation models of TFAM-expressing brown adipocytes could mimic the phenotype of TFAM TgTg mice, and proving their anti-obesity effect. We found that brown adipocytes secrete exosomes which enable self-activation in an autocrine and paracrine manner. The secretion was enhanced in TFAM TgTg brown adipocytes, resulting in a higher activation. These findings may lead to a promising treatment strategy for obesity through selective stimulation of exosome secretion.
Human TFAM overexpression in BAT promotes strong anti-obesity effects Increasing mitochondrial function in hTFAM TgTg mice facilitates EVs secretion Enhanced EV released in TgTg brown adipocytes induce self-differentiation/activation
Collapse
Affiliation(s)
- Masakazu Fujii
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Department of Internal Medicine, Fukuoka Prefectural Social Insurance Medical Association, Inatsuki Hospital, Kama 820-0207, Japan
- Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Corresponding author
| | - Daiki Setoyama
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kazuhito Gotoh
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yushi Dozono
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Mikako Yagi
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Department of Health Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Masataka Ikeda
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Tomomi Ide
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takeshi Uchiumi
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Department of Health Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Dongchon Kang
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| |
Collapse
|
|
15
|
Hamaoka T, Fu X, Tomonaga S, Hashimoto O, Murakami M, Funaba M. Stimulation of uncoupling protein 1 expression by β-alanine in brown adipocytes. Arch Biochem Biophys 2022; 727:109341. [PMID: 35777522 DOI: 10.1016/j.abb.2022.109341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 06/20/2022] [Accepted: 06/24/2022] [Indexed: 11/20/2022]
Abstract
Carnosine, which is abundant in meat, is a dipeptide composed of β-alanine and histidine, known to afford various health benefits. It has been suggested that carnosine can elicit an anti-obesity effect via induction and activation of brown/beige adipocytes responsible for non-shivering thermogenesis. However, the relationship between carnosine and brown/beige adipocytes has not been comprehensively elucidated. We hypothesized that β-alanine directly modulates brown/beige adipogenesis and performed an in vitro assessment to test this hypothesis. HB2 brown preadipocytes were differentiated using insulin from day 0. Cells were treated with various concentrations of β-alanine (12.5-100 μM) during adipogenesis (days 0-8) and differentiation (days 8-10). Then, cells were further stimulated with or without forskolin, an activator of the cAMP-dependent protein kinase pathway, on day 8 or day 10 for 4 h before harvesting. We observed that HB2 cells expressed molecules related to the transport and signal transduction of β-alanine. Treatment with β-alanine during brown adipogenesis dose-dependently enhanced forskolin-induced Ucp1 expression; this was not observed in differentiated brown adipocytes. Consistent with these findings, treatment with β-alanine during days 0-8 increased phosphorylation levels of CREB in forskolin-treated HB2 cells. In addition, β-alanine treatment during brown adipogenesis increased the expression of Pparα, known to induce brown/beige adipogenesis, in a dose-dependent manner. These findings revealed that β-alanine could target HB2 adipogenic cells and enhance forskolin-induced Ucp1 expression during brown adipogenesis, possibly by accelerating phosphorylation and activation of CREB. Thus, β-alanine, a carnosine-constituting amino acid, might directly act on brown adipogenic cells to stimulate energy expenditure.
Collapse
Affiliation(s)
- Tsukasa Hamaoka
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
| | - Xiajie Fu
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
| | - Shozo Tomonaga
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
| | - Osamu Hashimoto
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, 526-0829, Japan
| | - Masaru Murakami
- Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara, 252-5201, Japan
| | - Masayuki Funaba
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan.
| |
Collapse
|
|
16
|
Osorio-Conles Ó, Olbeyra R, Moizé V, Ibarzabal A, Giró O, Viaplana J, Jiménez A, Vidal J, de Hollanda A. Positive Effects of a Mediterranean Diet Supplemented with Almonds on Female Adipose Tissue Biology in Severe Obesity. Nutrients 2022; 14:nu14132617. [PMID: 35807797 PMCID: PMC9267991 DOI: 10.3390/nu14132617] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/19/2022] [Accepted: 06/21/2022] [Indexed: 02/06/2023] Open
Abstract
It has been suggested that weight-loss-independent Mediterranean diet benefits on cardiometabolic health and diabetes prevention may be mediated, at least in part, through the modulation of white adipose tissue (WAT) biology. This study aimed to evaluate the short-term effects of a dietary intervention based on the Mediterranean diet supplemented with almonds (MDSA) on the main features of obesity-associated WAT dysfunction. A total of 38 women with obesity were randomly assigned to a 3-month intervention with MDSA versus continuation of their usual dietary pattern. Subcutaneous (SAT) and visceral adipose tissue (VAT) biopsies were obtained before and after the dietary intervention, and at the end of the study period, respectively. MDSA favored the abundance of small adipocytes in WAT. In SAT, the expression of angiogenesis genes increased after MDSA intervention. In VAT, the expression of genes implicated in adipogenesis, angiogenesis, autophagy and fatty acid usage was upregulated. In addition, a higher immunofluorescence staining for PPARG, CD31+ cells and M2-like macrophages and increased ADRB1 and UCP2 protein contents were found compared to controls. Changes in WAT correlated with a significant reduction in circulating inflammatory markers and LDL-cholesterol levels. These results support a protective effect of a Mediterranean diet supplemented with almonds on obesity-related WAT dysfunction.
Collapse
Affiliation(s)
- Óscar Osorio-Conles
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (Ó.O.-C.); (V.M.); (J.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (R.O.); (O.G.); (A.J.)
| | - Romina Olbeyra
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (R.O.); (O.G.); (A.J.)
| | - Violeta Moizé
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (Ó.O.-C.); (V.M.); (J.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (R.O.); (O.G.); (A.J.)
- Obesity Unit, Endocrinology and Nutrition Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
| | - Ainitze Ibarzabal
- Gastrointestinal Surgery Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain;
| | - Oriol Giró
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (R.O.); (O.G.); (A.J.)
| | - Judith Viaplana
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (Ó.O.-C.); (V.M.); (J.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (R.O.); (O.G.); (A.J.)
| | - Amanda Jiménez
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (R.O.); (O.G.); (A.J.)
- Obesity Unit, Endocrinology and Nutrition Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Josep Vidal
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (Ó.O.-C.); (V.M.); (J.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (R.O.); (O.G.); (A.J.)
- Obesity Unit, Endocrinology and Nutrition Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
- Correspondence: (J.V.); (A.d.H.); Tel.: +34-93-227-20-12 (J.V.); +34-93-227-98-46 (A.d.H.); Fax: +34-93-227-55-89 (J.V. & A.d.H.)
| | - Ana de Hollanda
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (R.O.); (O.G.); (A.J.)
- Obesity Unit, Endocrinology and Nutrition Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Correspondence: (J.V.); (A.d.H.); Tel.: +34-93-227-20-12 (J.V.); +34-93-227-98-46 (A.d.H.); Fax: +34-93-227-55-89 (J.V. & A.d.H.)
| |
Collapse
|
|
17
|
He M, Yao J, Zhang Z, Zhang Y, Chen R, Gu Z, Huang X, Deng C, Zhou R, Fan J, Zhang B, Xie Y, Gao G, Sun T. Gold nanoclusters eliminate obesity induced by antipsychotics. Sci Rep 2022; 12:5502. [PMID: 35365730 PMCID: PMC8975852 DOI: 10.1038/s41598-022-09541-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 03/24/2022] [Indexed: 12/18/2022] Open
Abstract
Obesity induced by antipsychotics have plagued more than 20 million people worldwide. However, no drug is available to eliminate the obesity induced by antipsychotics. Here we examined the effect and potential mechanisms of a gold nanoclusters (AuNCs) modified by N-isobutyryl-L-cysteine on the obesity induced by olanzapine, the most prescribed but obesogenic antipsychotics, in a rat model. Our results showed that AuNCs completely prevented and reversed the obesity induced by olanzapine and improved glucose metabolism profile in rats. Further mechanism investigations revealed that AuNCs exert its anti-obesity function through inhibition of olanzapine-induced dysfunction of histamine H1 receptor and proopiomelanocortin signaling therefore reducing hyperphagia, and reversing olanzapine-induced inhibition of uncoupling-protein-1 signaling which increases thermogenesis. Together with AuNCs' good biocompatibility, these findings not only provide AuNCs as a promising nanodrug candidate for treating obesity induced by antipsychotics, but also open an avenue for the potential application of AuNCs-based nanodrugs in treating general obesity.
Collapse
Affiliation(s)
- Meng He
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, China
| | - Jing Yao
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, China
| | - Zijun Zhang
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, 430070, China
| | - Ying Zhang
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, China
| | - Rui Chen
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, 430070, China
| | - Zhenhua Gu
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, 430070, China
| | - XuFeng Huang
- School of Medicine and Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia
| | - Chao Deng
- School of Medicine and Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia
| | - Ruqin Zhou
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, China
| | - Jun Fan
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, China
| | - Baohua Zhang
- The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders, Capital Medical University, Beijing, 100191, China
| | - Yanqian Xie
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, China
| | - Guanbin Gao
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, 430070, China.
| | - Taolei Sun
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, China.
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, 430070, China.
| |
Collapse
|
|
18
|
Neohesperidin Dihydrochalcone and Neohesperidin Dihydrochalcone-O-Glycoside Attenuate Subcutaneous Fat and Lipid Accumulation by Regulating PI3K/AKT/mTOR Pathway In Vivo and In Vitro. Nutrients 2022; 14:nu14051087. [PMID: 35268062 PMCID: PMC8912486 DOI: 10.3390/nu14051087] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/17/2022] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Neohesperidin dihydrochalcone (NHDC), a semi-natural compound from bitter orange, is an intense sweetener. The anti-obesity effects of NHDC and its glycosidic compound, NHDC-O-glycoside (GNHDC), were investigated. C57BLKS/J db/db mice were supplemented with NHDC or GNHDC (100 mg/kg b.w.) for 4 weeks. Body weight gain, subcutaneous tissues, and total adipose tissues (sum of perirenal, visceral, epididymal, and subcutaneous adipose tissue) were decreased in the NHDC and GNHDC groups. Fatty acid uptake, lipogenesis, and adipogenesis-related genes were decreased, whereas β-oxidation and fat browning-related genes were up-regulated in the sweetener groups. Furthermore, both sweeteners suppressed the level of triacylglycerol accumulation, lipogenesis, adipogenesis, and proinflammatory cytokines in the 3T3-L1 cells. The PI3K/AKT/mTOR pathway was also down-regulated, and AMP-acttvated protein kinase (AMPK) was phosphorylated in the treatment groups. These results suggest that NHDC and GNHDC inhibited subcutaneous fat and lipid accumulation by regulating the PI3K/AKT/mTOR pathway and AMPK-related lipogenesis and fat browning.
Collapse
|
|
19
|
Zhao J, Gomes D, Jin L, Mathis SP, Li X, Rouchka EC, Bodduluri H, Conklin DJ, O'Toole TE. Polystyrene bead ingestion promotes adiposity and cardiometabolic disease in mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 232:113239. [PMID: 35093814 PMCID: PMC8860873 DOI: 10.1016/j.ecoenv.2022.113239] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/18/2022] [Accepted: 01/24/2022] [Indexed: 05/05/2023]
Abstract
Vast amounts of plastic materials are produced in the modern world and despite recycling efforts, large amounts are disposed in water systems and landfills. Under these storage conditions, physical weathering and photochemical processes break down these materials into smaller particles of the micro- and nano-scale. In addition, ecosystems can be contaminated with plastic particles which are manufactured in these size ranges for commercial purposes. Independent of source, microplastics are abundant in the environment and have found their way into water supplies and the food cycle where human exposure is inevitable. Nevertheless, the health consequences of microplastic ingestion, inhalation, or absorption are largely unknown. In this study we sought to determine if ingestion of microplastics promoted pre-clinical cardiovascular disease (CVD). To do this, we supplied mice with normal drinking water or that supplemented with polystyrene beads of two different sizes (0.5 µm and 5 µm) and two different doses (0.1 μg/ml and 1 μg/ml) each for 12 weeks and measured several indices of metabolism and glucose homeostasis. As early as 3 weeks of consumption, we observed an accelerated weight gain with a corresponding increase in body fat for some exposure groups versus the control mice. Some exposure groups demonstrated increased levels of fasting plasma glucose. Those mice consuming the smaller sized beads (0.5 µm) at the higher dose (1 μg/ml), had increased levels of fasting plasma insulin and higher homeostatic model assessment of insulin resistance (HOMA-IR) scores as well. This was accompanied by changes in the gut microbiome consistent with an obese phenotype. Using samples of perivascular adipose tissue collected from the same group, we observed changes in gene expression consistent with increased adipogenesis. These results suggest that ingestion of polystyrene beads promotes a cardiometabolic disease phenotype and thus may be an unrecognized risk factor for CVD.
Collapse
Affiliation(s)
- Jingjing Zhao
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Daniel Gomes
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA
| | - Lexiao Jin
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Steven P Mathis
- Department of Microbiology and Immunology, James Graham Brown Cancer Center and Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville, Louisville, KY, USA
| | - Xiaohong Li
- Kentucky Biomedical Research Infrastructure Network Bioinformatics Core, University of Louisville, Louisville, KY, USA; Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY, USA
| | - Eric C Rouchka
- Kentucky Biomedical Research Infrastructure Network Bioinformatics Core, University of Louisville, Louisville, KY, USA; Department of Computer Science and Engineering, University of Louisville, Louisville, KY, USA
| | - Haribabu Bodduluri
- Department of Microbiology and Immunology, James Graham Brown Cancer Center and Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville, Louisville, KY, USA
| | - Daniel J Conklin
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Timothy E O'Toole
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, KY, USA.
| |
Collapse
|
|
20
|
SENP2 suppresses browning of white adipose tissues by de-conjugating SUMO from C/EBPβ. Cell Rep 2022; 38:110408. [PMID: 35196497 DOI: 10.1016/j.celrep.2022.110408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/26/2021] [Accepted: 01/27/2022] [Indexed: 11/20/2022] Open
Abstract
The adipose tissue is a key site regulating energy metabolism. One of the contributing factors behind this is browning of white adipose tissue (WAT). However, knowledge of the intracellular determinants of the browning process remains incomplete. By generating adipocyte-specific Senp2 knockout (Senp2-aKO) mice, here we show that SENP2 negatively regulates browning by de-conjugating small ubiquitin-like modifiers from C/EBPβ. Senp2-aKO mice are resistant to diet-induced obesity due to increased energy expenditure and heat production. Senp2 knockout promotes beige adipocyte accumulation in inguinal WAT by upregulation of thermogenic gene expression. In addition, SENP2 knockdown promotes thermogenic adipocyte differentiation of precursor cells isolated from inguinal and epididymal WATs. Mechanistically, sumoylated C/EBPβ, a target of SENP2, suppresses expression of HOXC10, a browning inhibitor, by recruiting a transcriptional repressor DAXX. These findings indicate that a SENP2-C/EBPβ-HOXC10 axis operates for the control of beige adipogenesis in inguinal WAT.
Collapse
|
|
21
|
Annunziata C, Pirozzi C, Lama A, Senzacqua M, Comella F, Bordin A, Monnolo A, Pelagalli A, Ferrante MC, Mollica MP, Iossa A, De Falco E, Mattace Raso G, Cinti S, Giordano A, Meli R. Palmitoylethanolamide Promotes White-to-Beige Conversion and Metabolic Reprogramming of Adipocytes: Contribution of PPAR-α. Pharmaceutics 2022; 14:338. [PMID: 35214069 PMCID: PMC8880285 DOI: 10.3390/pharmaceutics14020338] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/21/2022] [Accepted: 01/25/2022] [Indexed: 02/04/2023] Open
Abstract
The potential role of brown and beige adipose tissue against obesity has been recognized. Browning, or beiging of white adipose tissue (WAT) is associated with the remodeling of adipocytes and the improvement of their metabolic and secretory functions. Here, palmitoylethanolamide (PEA) restore the plasticity of brown and white adipocytes impaired in mice on a high-fat diet (HFD). Young male C57Bl/6J mice were fed with control (STD) diet or HFD for 12 weeks. Ultramicronized PEA (30 mg/kg/die p.o.) was administered for an additional 7 weeks, together with HFD. PEA recovered interscapular brown fat morphology and function, increasing UCP1 positivity, noradrenergic innervation, and inducing the mRNA transcription of several specialized thermogenic genes. PEA promotes the beige-conversion of the subcutaneous WAT, increasing thermogenic markers and restoring leptin signaling and tissue hormone sensitivity. The pivotal role of lipid-sensing peroxisome proliferator-activated receptor (PPAR)-α in PEA effects was determined in mature 3T3-L1. Moreover, PEA improved mitochondrial bioenergetics in mature adipocytes measured by a Seahorse analyzer and induced metabolic machinery via AMPK phosphorylation. All these outcomes were dampened by the receptor antagonist GW6471. Finally, PEA induced adipogenic differentiation and increased AMPK phosphorylation in human adipose-derived stromal cells (ASCs) obtained from subcutaneous WAT of normal-weight patients and patients with obesity. We identify PEA and PPAR-α activation as the main mechanism by which PEA can rewire energy-storing white into energy-consuming brown-like adipocytes via multiple and converging effects that restore WAT homeostasis and metabolic flexibility.
Collapse
Affiliation(s)
- Chiara Annunziata
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; (C.A.); (C.P.); (A.L.); (F.C.); (G.M.R.)
| | - Claudio Pirozzi
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; (C.A.); (C.P.); (A.L.); (F.C.); (G.M.R.)
| | - Adriano Lama
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; (C.A.); (C.P.); (A.L.); (F.C.); (G.M.R.)
| | - Martina Senzacqua
- Department of Experimental and Clinical Medicine, Marche Polytechnic University, 60020 Ancona, Italy; (M.S.); (S.C.); (A.G.)
| | - Federica Comella
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; (C.A.); (C.P.); (A.L.); (F.C.); (G.M.R.)
| | - Antonella Bordin
- Department of Medical-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University of Rome, 04100 Latina, Italy; (A.B.); (A.I.); (E.D.F.)
| | - Anna Monnolo
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, 80137 Naples, Italy; (A.M.); (M.C.F.)
| | - Alessandra Pelagalli
- Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy;
- Institute of Biostructure and Bioimaging, National Research Council (CNR), 80134 Naples, Italy
| | - Maria Carmela Ferrante
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, 80137 Naples, Italy; (A.M.); (M.C.F.)
| | - Maria Pina Mollica
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy;
| | - Angelo Iossa
- Department of Medical-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University of Rome, 04100 Latina, Italy; (A.B.); (A.I.); (E.D.F.)
| | - Elena De Falco
- Department of Medical-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University of Rome, 04100 Latina, Italy; (A.B.); (A.I.); (E.D.F.)
- Mediterranea Cardiocenter, 80122 Naples, Italy
| | - Giuseppina Mattace Raso
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; (C.A.); (C.P.); (A.L.); (F.C.); (G.M.R.)
| | - Saverio Cinti
- Department of Experimental and Clinical Medicine, Marche Polytechnic University, 60020 Ancona, Italy; (M.S.); (S.C.); (A.G.)
| | - Antonio Giordano
- Department of Experimental and Clinical Medicine, Marche Polytechnic University, 60020 Ancona, Italy; (M.S.); (S.C.); (A.G.)
| | - Rosaria Meli
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; (C.A.); (C.P.); (A.L.); (F.C.); (G.M.R.)
| |
Collapse
|
|
22
|
Mishra BK, Madhu SV, Aslam M, Agarwal V, Banerjee BD. Adipose tissue expression of UCP1 and PRDM16 genes and their association with postprandial triglyceride metabolism and glucose intolerance. Diabetes Res Clin Pract 2021; 182:109115. [PMID: 34718051 DOI: 10.1016/j.diabres.2021.109115] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 08/28/2021] [Accepted: 10/15/2021] [Indexed: 12/01/2022]
Abstract
AIMS UCP1 and PRDM16 genes, primarily involved in browning of adipose tissue that can affect lipid metabolism are also associated with diabetes risk. Therefore, we planned to study the adipose tissue expression of UCP1 and PRDM 16 genes in subjects with glucose intolerance to find out its association with postprandial triglyceride (PPTg) measures and T2DM. METHODS A total of 30 subjects were recruited in three groups i.e., NGT, prediabetes and T2DM (NDDM + known T2DM) who were matched for age, sex and BMI. An 8-hour standardized fat challenge test was performed to study lipemic responses. UCP1 and PRDM16 genes quantification in adipose tissue was performed by real-time PCR followed by SDS PAGE. RESULTS UCP1 gene expression in SAT was significantly lower in T2DM and prediabetes as compared to NGT group while PRDM16 gene expression was significantly lower in T2DM group as compared to NGT group. UCP1 gene expression correlated with PPTg measures as well as with glycaemic measures while PRDM16 gene expression correlated with glycaemic measures only. CONCLUSION This study found downregulation of PRDM16 and UCP1 gene expression in SAT in subjects with glucose intolerance. The association of UCP1 gene expression with PPTg dysmetabolism may contribute to greater predisposition to T2DM.
Collapse
Affiliation(s)
- B K Mishra
- Department of Endocrinology, University College of Medical Sciences & GTB Hospital, University of Delhi, India
| | - S V Madhu
- Department of Endocrinology, University College of Medical Sciences & GTB Hospital, University of Delhi, India.
| | - M Aslam
- Department of Endocrinology, University College of Medical Sciences & GTB Hospital, University of Delhi, India
| | - V Agarwal
- Department of Surgery, University College of Medical Sciences & GTB Hospital, University of Delhi, India
| | - B D Banerjee
- Department of Biochemistry, University College of Medical Sciences & GTB Hospital, University of Delhi, India
| |
Collapse
|
|
23
|
Yang H, Ma C, Zi Y, Zhang M, Liu Y, Wu K, Gao F. Effects of maternal undernutrition during late pregnancy on the regulatory factors involved in growth and development in ovine fetal perirenal brown adipose tissue. Anim Biosci 2021; 35:1010-1020. [PMID: 34530507 PMCID: PMC9271387 DOI: 10.5713/ab.21.0199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 08/27/2021] [Indexed: 12/02/2022] Open
Abstract
Objective The experiment was conducted to evaluate the effects of maternal undernutrition during late pregnancy on the expressions of genes involved in growth and development in ovine fetal perirenal brown adipose tissue (BAT). Methods Eighteen ewes with singleton fetuses were allocated to three groups at day 90 of pregnancy: restricted group 1 (RG1, 0.33 MJ metabolisable energy [ME]/kg body weight [BW]0.75/d, n = 6), restricted group 2 (RG2, 0.18 MJ ME/kg BW0.75/d, n = 6), and a control group (CG, ad libitum, 0.67 MJ ME/kg BW0.75/d, n = 6). The fetuses were removed at day 140 of pregnancy. All data were analyzed by using the analysis of variance procedure. Results The perirenal fat weight (p = 0.0077) and perirenal fat growth rate (p = 0.0074) were reduced in RG2 compared to CG. In fetal perirenal BAT, the protein level of uncoupling protein 1 (UCP1) (p = 0.0001) was lower in RG1 and RG2 compared with CG and UCP1 mRNA expression (p = 0.0265) was decreased in RG2. The protein level of myogenic factor 5 (Myf5) was also decreased in RG2 (p = 0.0001). In addition, mRNA expressions of CyclinA (p = 0.0109), CyclinB (p = 0.0019), CyclinD (p = 0.0015), cyclin-dependent kinase 1 (CDK1) (p = 0.0001), E2F transcription factor 1 (E2F1) (p = 0.0323), E2F4 (p = 0.0101), and E2F5 (p = 0.0018) were lower in RG1 and RG2. There were decreased protein expression of peroxisome proliferator-activated receptor-γ (PPARγ) (p = 0.0043) and mRNA expression of CCAAT/enhancer-binding protein-α (C/EBPα) (p = 0.0307) in RG2 and decreased PPARγ mRNA expression (p = 0.0008) and C/EBPα protein expression (p = 0.0015) in both RG2 and RG1. Furthermore, mRNA expression of bone morphogenetic protein 4 (BMP4) (p = 0.0083) and BMP7 (p = 0.0330) decreased in RG2 and peroxisome proliferator-activated receptor co-activator-1α (PGC-1α) reduced in RG2 and RG1. Conclusion Our observations support that repression of regulatory factors promoting differentiation and development results in the inhibition of BAT maturation in fetal perirenal fat during late pregnancy with maternal undernutrition.
Collapse
Affiliation(s)
- Huan Yang
- College of Animal Science, Inner Mongolia Key Laboratory of animal nutrition and feed, Inner Mongolia Agricultural University, Hohhot, 010018 China
| | - Chi Ma
- College of Animal Science, Inner Mongolia Key Laboratory of animal nutrition and feed, Inner Mongolia Agricultural University, Hohhot, 010018 China
| | - Yang Zi
- College of Animal Science, Inner Mongolia Key Laboratory of animal nutrition and feed, Inner Mongolia Agricultural University, Hohhot, 010018 China
| | - Min Zhang
- College of Animal Science, Inner Mongolia Key Laboratory of animal nutrition and feed, Inner Mongolia Agricultural University, Hohhot, 010018 China
| | - Yingchun Liu
- College of Life Science, Inner Mongolia Key Laboratory of Biomanufacturing, Inner Mongolia Agricultural University, Hohhot, 010018 China
| | - Kaifeng Wu
- College of Life Science, Inner Mongolia Key Laboratory of Biomanufacturing, Inner Mongolia Agricultural University, Hohhot, 010018 China
| | - Feng Gao
- College of Animal Science, Inner Mongolia Key Laboratory of animal nutrition and feed, Inner Mongolia Agricultural University, Hohhot, 010018 China.,Key Laboratory of Mutton Sheep Genetics and Breeding of Ministry of Agriculture, Hohhot, 010018 China
| |
Collapse
|
|
24
|
Mig-6 is essential for glucose homeostasis and thermogenesis in brown adipose tissue. Biochem Biophys Res Commun 2021; 572:92-97. [PMID: 34358969 DOI: 10.1016/j.bbrc.2021.07.088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 01/06/2023]
Abstract
Brown adipose tissue (BAT) is an anti-obese and anti-diabetic tissue that stimulates energy expenditure in the form of adaptive thermogenesis through uncoupling protein 1 (UCP1). Mitogen-inducible gene-6 (Mig-6) is a negative regulator of epidermal growth factor receptor (EGFR) that interacts with many cellular partners and has multiple cellular functions. We have recently reported that Mig-6 is associated with diabetes and metabolic syndrome. However, its function in BAT is unknown. We generated a brown adipocyte-specific Mig-6 knock-in mouse (BKI) to examine the role of Mig-6 in BAT. Mig-6 BKI mice had improved glucose tolerance on a normal chow diet. Mig-6 BKI mice also revealed activated thermogenesis and the size of the BAT lipid droplets was reduced. Additionally, Mig-6 regulated cAMP-PKA signaling-induced UCP1 expression in brown adipocytes. Taken together, these results demonstrate that Mig-6 affects glucose tolerance and thermogenesis in BAT.
Collapse
|
|
25
|
Zhang C, Zhao Z, Liu H, Yao S, Zhao D. Weighted Gene Co-expression Network Analysis Identified a Novel Thirteen-Gene Signature Associated With Progression, Prognosis, and Immune Microenvironment of Colon Adenocarcinoma Patients. Front Genet 2021; 12:657658. [PMID: 34322151 PMCID: PMC8312261 DOI: 10.3389/fgene.2021.657658] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 06/22/2021] [Indexed: 02/05/2023] Open
Abstract
Colon adenocarcinoma (COAD) is one of the most common malignant tumors and has high migration and invasion capacity. In this study, we attempted to establish a multigene signature for predicting the prognosis of COAD patients. Weighted gene co-expression network analysis and differential gene expression analysis methods were first applied to identify differentially co-expressed genes between COAD tissues and normal tissues from the Cancer Genome Atlas (TCGA)-COAD dataset and GSE39582 dataset, and a total of 309 overlapping genes were screened out. Then, our study employed TCGA-COAD cohort as the training dataset and an independent cohort by merging the GES39582 and GSE17536 datasets as the testing dataset. After univariate and multivariate Cox regression analyses were performed for these overlapping genes and overall survival (OS) of COAD patients in the training dataset, a 13-gene signature was constructed to divide COAD patients into high- and low-risk subgroups with significantly different OS. The testing dataset exhibited the same results utilizing the same predictive signature. The area under the curve of receiver operating characteristic analysis for predicting OS in the training and testing datasets were 0.789 and 0.868, respectively, which revealed the enhanced predictive power of the signature. Multivariate Cox regression analysis further suggested that the 13-gene signature could independently predict OS. Among the 13 prognostic genes, NAT1 and NAT2 were downregulated with deep deletions in tumor tissues in multiple COAD cohorts and exhibited significant correlations with poorer OS based on the GEPIA database. Notably, NAT1 and NAT2 expression levels were positively correlated with infiltrating levels of CD8+ T cells and dendritic cells, exhibiting a foundation for further research investigating the antitumor immune roles played by NAT1 and NAT2 in COAD. Taken together, the results of our study showed that the 13-gene signature could efficiently predict OS and that NAT1 and NAT2 could function as biomarkers for prognosis and the immune response in COAD.
Collapse
Affiliation(s)
- Cangang Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Zhe Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China (Ministry of Education), College of Life Science, Northwest University, Xi’an, China
| | - Haibo Liu
- Department of Hematology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Shukun Yao
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Dongyan Zhao
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| |
Collapse
|
|
26
|
Zhao J, Tao C, Chen C, Wang Y, Liu T. Formation of thermogenic adipocytes: What we have learned from pigs. FUNDAMENTAL RESEARCH 2021. [DOI: 10.1016/j.fmre.2021.05.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
|
|
27
|
Worley BL, Auen T, Arnold AC, Monia BP, Hempel N, Czyzyk TA. Antisense oligonucleotide-mediated knockdown of Mpzl3 attenuates the negative metabolic effects of diet-induced obesity in mice. Physiol Rep 2021; 9:e14853. [PMID: 33991450 PMCID: PMC8123547 DOI: 10.14814/phy2.14853] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 04/05/2021] [Indexed: 02/06/2023] Open
Abstract
Previously, we demonstrated that global knockout (KO) of the gene encoding myelin protein zero‐like 3 (Mpzl3) results in reduced body weight and adiposity, increased energy expenditure, and reduced hepatic lipid synthesis in mice. These mice also exhibit cyclic and progressive alopecia which may contribute to the observed hypermetabolic phenotype. The goal of the current study was to determine if acute and peripherally restricted knockdown of Mpzl3 could ameliorate the negative metabolic effects of exposure to a high‐fat and sucrose, energy‐dense (HED) diet similar to what was observed in global Mpzl3 KO mice in the absence of a skin phenotype. Mpzl3 antisense oligonucleotide (ASO) administration dose‐dependently decreased fat mass and circulating lipids in HED‐fed C57BL/6N mice. These changes were accompanied by a decrease in respiratory exchange ratio, a reduction in energy expenditure and food intake, a decrease in expression of genes regulating de novo lipogenesis in white adipose tissue, and an upregulation of genes associated with steroid hormone biosynthesis in liver, thermogenesis in brown adipose tissue and fatty acid transport in skeletal muscle. These data demonstrate that resistance to the negative metabolic effects of HED is a direct effect of Mpzl3 knockdown, rather than compensatory changes that could be associated with deletion of Mpzl3 during development in global KO mice. Inhibiting MPZL3 could be a potential therapeutic approach for the treatment of obesity and associated dyslipidemia.
Collapse
Affiliation(s)
- Beth L Worley
- Department of Anesthesiology & Perioperative Medicine, Penn State University College of Medicine, Hershey, PA, USA.,Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, USA.,Biomedical Sciences Program, Penn State University College of Medicine, Hershey, PA, USA
| | - Thomas Auen
- Department of Anesthesiology & Perioperative Medicine, Penn State University College of Medicine, Hershey, PA, USA
| | - Amy C Arnold
- Department of Neural & Behavioral Sciences, Penn State University College of Medicine, Hershey, PA, USA
| | | | - Nadine Hempel
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, USA
| | - Traci A Czyzyk
- Department of Anesthesiology & Perioperative Medicine, Penn State University College of Medicine, Hershey, PA, USA.,Department of Neural & Behavioral Sciences, Penn State University College of Medicine, Hershey, PA, USA
| |
Collapse
|
|
28
|
Molinari F, Feraco A, Mirabilii S, Saladini S, Sansone L, Vernucci E, Tomaselli G, Marzolla V, Rotili D, Russo MA, Ricciardi MR, Tafuri A, Mai A, Caprio M, Tafani M, Armani A. SIRT5 Inhibition Induces Brown Fat-Like Phenotype in 3T3-L1 Preadipocytes. Cells 2021; 10:cells10051126. [PMID: 34066961 PMCID: PMC8148511 DOI: 10.3390/cells10051126] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/03/2021] [Accepted: 05/05/2021] [Indexed: 12/15/2022] Open
Abstract
Brown adipose tissue (BAT) activity plays a key role in regulating systemic energy. The activation of BAT results in increased energy expenditure, making this tissue an attractive pharmacological target for therapies against obesity and type 2 diabetes. Sirtuin 5 (SIRT5) affects BAT function by regulating adipogenic transcription factor expression and mitochondrial respiration. We analyzed the expression of SIRT5 in the different adipose depots of mice. We treated 3T3-L1 preadipocytes and mouse primary preadipocyte cultures with the SIRT5 inhibitor MC3482 and investigated the effects of this compound on adipose differentiation and function. The administration of MC3482 during the early stages of differentiation promoted the expression of brown adipocyte and mitochondrial biogenesis markers. Upon treatment with MC3482, 3T3-L1 adipocytes showed an increased activation of the AMP-activated protein kinase (AMPK), which is known to stimulate brown adipocyte differentiation. This effect was paralleled by an increase in autophagic/mitophagic flux and a reduction in lipid droplet size, mediated by a higher lipolytic rate. Of note, MC3482 increased the expression and the activity of adipose triglyceride lipase, without modulating hormone-sensitive lipase. Our findings reveal that SIRT5 inhibition stimulates brown adipogenesis in vitro, supporting this approach as a strategy to stimulate BAT and counteract obesity.
Collapse
Affiliation(s)
- Francesca Molinari
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (F.M.); (S.S.); (M.T.)
| | - Alessandra Feraco
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00163 Rome, Italy; (A.F.); (V.M.); (M.C.)
| | - Simone Mirabilii
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (S.M.); (M.R.R.); (A.T.)
| | - Serena Saladini
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (F.M.); (S.S.); (M.T.)
| | - Luigi Sansone
- Department of Cellular and Molecular Pathology, IRCCS San Raffaele, 00166 Rome, Italy; (L.S.); (G.T.); (M.A.R.)
| | - Enza Vernucci
- Department of Cardiovascular, Nephrologic, Anesthesiologic and Geriatric Sciences, Sapienza University of Rome, 00161 Rome, Italy;
| | - Giada Tomaselli
- Department of Cellular and Molecular Pathology, IRCCS San Raffaele, 00166 Rome, Italy; (L.S.); (G.T.); (M.A.R.)
| | - Vincenzo Marzolla
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00163 Rome, Italy; (A.F.); (V.M.); (M.C.)
| | - Dante Rotili
- Department of Chemistry and Technology of Drugs, Sapienza University, P.le Aldo Moro 5, 00185 Rome, Italy; (D.R.); (A.M.)
| | - Matteo A. Russo
- Department of Cellular and Molecular Pathology, IRCCS San Raffaele, 00166 Rome, Italy; (L.S.); (G.T.); (M.A.R.)
- MEBIC Consortium, San Raffaele Rome Open University, 00166 Rome, Italy
| | - Maria Rosaria Ricciardi
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (S.M.); (M.R.R.); (A.T.)
| | - Agostino Tafuri
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (S.M.); (M.R.R.); (A.T.)
- Hematology, “Sant’ Andrea” University Hospital, Sapienza University of Rome, 00189 Rome, Italy
| | - Antonello Mai
- Department of Chemistry and Technology of Drugs, Sapienza University, P.le Aldo Moro 5, 00185 Rome, Italy; (D.R.); (A.M.)
| | - Massimiliano Caprio
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00163 Rome, Italy; (A.F.); (V.M.); (M.C.)
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
| | - Marco Tafani
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (F.M.); (S.S.); (M.T.)
| | - Andrea Armani
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00163 Rome, Italy; (A.F.); (V.M.); (M.C.)
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
- Correspondence:
| |
Collapse
|
|
29
|
Ito K, Schneeberger M, Gerber A, Jishage M, Marchildon F, Maganti AV, Cohen P, Friedman JM, Roeder RG. Critical roles of transcriptional coactivator MED1 in the formation and function of mouse adipose tissues. Genes Dev 2021; 35:729-748. [PMID: 33888560 PMCID: PMC8091968 DOI: 10.1101/gad.346791.120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 03/16/2021] [Indexed: 01/12/2023]
Abstract
In this study, Ito et al. sought to understand the precise roles of MED1, and its various domains, at various stages of adipogenesis and in adipose tissue. Using multiple genetic approaches to assess requirements for MED1 in adipocyte formation and function in mice, they show that MED1 is indeed essential for the differentiation and/or function of both brown and white adipocytes, as its absence in these cells leads to, respectively, defective brown fat function and lipodystrophy. The MED1 subunit has been shown to mediate ligand-dependent binding of the Mediator coactivator complex to multiple nuclear receptors, including the adipogenic PPARγ, and to play an essential role in ectopic PPARγ-induced adipogenesis of mouse embryonic fibroblasts. However, the precise roles of MED1, and its various domains, at various stages of adipogenesis and in adipose tissue have been unclear. Here, after establishing requirements for MED1, including specific domains, for differentiation of 3T3L1 cells and both primary white and brown preadipocytes, we used multiple genetic approaches to assess requirements for MED1 in adipocyte formation, maintenance, and function in mice. We show that MED1 is indeed essential for the differentiation and/or function of both brown and white adipocytes, as its absence in these cells leads to, respectively, defective brown fat function and lipodystrophy. This work establishes MED1 as an essential transcriptional coactivator that ensures homeostatic functions of adipocytes.
Collapse
Affiliation(s)
- Keiichi Ito
- Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA
| | - Marc Schneeberger
- Laboratory of Molecular Genetics, The Rockefeller University, New York, New York 10065, USA
| | - Alan Gerber
- Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA
| | - Miki Jishage
- Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA
| | - Francois Marchildon
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York 10065, USA
| | - Aarthi V Maganti
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York 10065, USA
| | - Paul Cohen
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York 10065, USA
| | - Jeffrey M Friedman
- Laboratory of Molecular Genetics, The Rockefeller University, New York, New York 10065, USA
| | - Robert G Roeder
- Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA
| |
Collapse
|
|
30
|
Cho YK, Son Y, Saha A, Kim D, Choi C, Kim M, Park JH, Im H, Han J, Kim K, Jung YS, Yun J, Bae EJ, Seong JK, Lee MO, Lee S, Granneman JG, Lee YH. STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure. Nat Metab 2021; 3:428-441. [PMID: 33758424 DOI: 10.1038/s42255-021-00362-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 02/12/2021] [Indexed: 11/08/2022]
Abstract
Obesity reduces adipocyte mitochondrial function, and expanding adipocyte oxidative capacity is an emerging strategy to improve systemic metabolism. Here, we report that serine/threonine-protein kinase 3 (STK3) and STK4 are key physiological suppressors of mitochondrial capacity in brown, beige and white adipose tissues. Levels of STK3 and STK4, kinases in the Hippo signalling pathway, are greater in white than brown adipose tissues, and levels in brown adipose tissue are suppressed by cold exposure and greatly elevated by surgical denervation. Genetic inactivation of Stk3 and Stk4 increases mitochondrial mass and function, stabilizes uncoupling protein 1 in beige adipose tissue and confers resistance to metabolic dysfunction induced by high-fat diet feeding. Mechanistically, STK3 and STK4 increase adipocyte mitophagy in part by regulating the phosphorylation and dimerization status of the mitophagy receptor BNIP3. STK3 and STK4 expression levels are elevated in human obesity, and pharmacological inhibition improves metabolic profiles in a mouse model of obesity, suggesting STK3 and STK4 as potential targets for treating obesity-related diseases.
Collapse
Affiliation(s)
- Yoon Keun Cho
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Yeonho Son
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Abhirup Saha
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Doeun Kim
- BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Cheoljun Choi
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Minsu Kim
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Ji-Hyun Park
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Hyeonyeong Im
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Juhyeong Han
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Kyungmin Kim
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Young-Suk Jung
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Jeanho Yun
- Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Republic of Korea
| | - Eun Ju Bae
- College of Pharmacy, Chonbuk National University, Jeonju, Republic of Korea
| | - Je Kyung Seong
- Laboratory of Developmental Biology and Genomics, BK21 Plus Program for Advanced Veterinary Science, Research Institute for Veterinary Science, College of Veterinary Medicine, and Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea
| | - Mi-Ock Lee
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Sangkyu Lee
- BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - James G Granneman
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
- Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI, USA
| | - Yun-Hee Lee
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
- Bio-Max Institute, Seoul National University, Seoul, Republic of Korea.
| |
Collapse
|
|
31
|
Auclair M, Roblot N, Capel E, Fève B, Antoine B. Pharmacological modulation of RORα controls fat browning, adaptive thermogenesis, and body weight in mice. Am J Physiol Endocrinol Metab 2021; 320:E219-E233. [PMID: 33252251 PMCID: PMC8260366 DOI: 10.1152/ajpendo.00131.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Beiging is an attractive therapeutic strategy to fight against obesity and its side metabolic complications. The loss of function of the nuclear transcription factor RORα has been related to a lean phenotype with higher thermogenesis in sg/sg mice lacking this protein. Here we show that pharmacological modulation of RORα activity exerts reciprocal and cell-autonomous effect on UCP1 expression ex vivo, in cellulo, and in vivo. The RORα inverse-agonist SR3335 upregulated UCP1 expression in brown and subcutaneous white adipose tissue (scWAT) explants of wild-type (WT) mice, whereas the RORα agonist SR1078 had the opposite effect. We confirmed the reciprocal action of these synthetic RORα ligands on gene expression, mitochondrial mass, and uncoupled oxygen consumption rate in cultured murine and human adipocytes. Time course analysis revealed stepwise variation in gene expression, first of TLE3, an inhibitor of the thermogenic program, followed by a reciprocal effect on PRDM16 and UCP1. Finally, RORα ligands were shown to be useful tools to modulate in vivo UCP1 expression in scWAT with associated changes in this fat depot mass. SR3335 and SR1078 provoked the opposite effects on the WT mice body weight, but without any effect on sg/sg mice. This slimming effect of SR3335 was related to an increased adaptive thermogenesis of the mice, as assessed by the rectal temperature of cold-stressed mice and induction of UCP1 in scWAT, as well as by indirect calorimetry in presence or not of a β3-adrenoceptor agonist. These data confirmed that RORα ligands could be useful tools to modulate thermogenesis and energy homeostasis.NEW & NOTEWORTHY The regulation of adipose tissue browning was not fully deciphered and required further studies explaining how the regulation of this process may be of interest for tackling obesity and related metabolic disorders. Our data confirmed the involvement of the transcription factor RORα in the regulation of nonshivering thermogenesis, and importantly, revealed the possibility to in vivo modulate its activity by synthetic ligands with beneficial consequences on fat mass and body weight of the mice.
Collapse
MESH Headings
- Adipocytes/drug effects
- Adipocytes/physiology
- Adipose Tissue, Brown/drug effects
- Adipose Tissue, Brown/physiology
- Adipose Tissue, White/drug effects
- Adipose Tissue, White/physiology
- Adult
- Animals
- Benzamides/pharmacology
- Body Weight/drug effects
- Cell Transdifferentiation/drug effects
- Cells, Cultured
- Cold-Shock Response/drug effects
- Cold-Shock Response/physiology
- Female
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Mutant Strains
- Nuclear Receptor Subfamily 1, Group F, Member 1/agonists
- Nuclear Receptor Subfamily 1, Group F, Member 1/physiology
- Sulfonamides/pharmacology
- Thermogenesis/drug effects
- Thiazoles/pharmacology
- Thiophenes/pharmacology
Collapse
Affiliation(s)
- Martine Auclair
- Centre de Recherche Saint-Antoine UMR_S938, Sorbonne Université-INSERM, Paris, France
| | - Natacha Roblot
- Centre de Recherche Saint-Antoine UMR_S938, Sorbonne Université-INSERM, Paris, France
| | - Emilie Capel
- Centre de Recherche Saint-Antoine UMR_S938, Sorbonne Université-INSERM, Paris, France
| | - Bruno Fève
- Centre de Recherche Saint-Antoine UMR_S938, Sorbonne Université-INSERM, Paris, France
- AP-HP, Service d'Endocrinologie, Hôpital Saint-Antoine, Paris, France
| | - Bénédicte Antoine
- Centre de Recherche Saint-Antoine UMR_S938, Sorbonne Université-INSERM, Paris, France
| |
Collapse
|
|
32
|
Christofides A, Konstantinidou E, Jani C, Boussiotis VA. The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metabolism 2021; 114:154338. [PMID: 32791172 PMCID: PMC7736084 DOI: 10.1016/j.metabol.2020.154338] [Citation(s) in RCA: 369] [Impact Index Per Article: 92.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/06/2020] [Accepted: 07/24/2020] [Indexed: 02/07/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors of nuclear hormone receptor superfamily that regulate energy metabolism. Currently, three PPAR subtypes have been identified: PPARα, PPARγ, and PPARβ/δ. PPARα and PPARδ are highly expressed in oxidative tissues and regulate genes involved in substrate delivery and oxidative phosphorylation (OXPHOS) and regulation of energy homeostasis. In contrast, PPARγ is more important in lipogenesis and lipid synthesis, with highest expression levels in white adipose tissue (WAT). In addition to tissues regulating whole body energy homeostasis, PPARs are expressed in immune cells and have an emerging critical role in immune cell differentiation and fate commitment. In this review, we discuss the actions of PPARs in the function of the innate and the adaptive immune system and their implications in immune-mediated inflammatory conditions.
Collapse
Affiliation(s)
- Anthos Christofides
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Eirini Konstantinidou
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Chinmay Jani
- Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Mt. Auburn Hospital, Cambridge, MA 02138, United States of America
| | - Vassiliki A Boussiotis
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America.
| |
Collapse
|
|
33
|
Thermogenic adipocytes: lineage, function and therapeutic potential. Biochem J 2020; 477:2071-2093. [PMID: 32539124 PMCID: PMC7293110 DOI: 10.1042/bcj20200298] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/13/2020] [Accepted: 05/15/2020] [Indexed: 12/12/2022]
Abstract
Metabolic inflexibility, defined as the inability to respond or adapt to metabolic demand, is now recognised as a driving factor behind many pathologies associated with obesity and the metabolic syndrome. Adipose tissue plays a pivotal role in the ability of an organism to sense, adapt to and counteract environmental changes. It provides a buffer in times of nutrient excess, a fuel reserve during starvation and the ability to resist cold-stress through non-shivering thermogenesis. Recent advances in single-cell RNA sequencing combined with lineage tracing, transcriptomic and proteomic analyses have identified novel adipocyte progenitors that give rise to specialised adipocytes with diverse functions, some of which have the potential to be exploited therapeutically. This review will highlight the common and distinct functions of well-known adipocyte populations with respect to their lineage and plasticity, as well as introducing the most recent members of the adipocyte family and their roles in whole organism energy homeostasis. Finally, this article will outline some of the more preliminary findings from large data sets generated by single-cell transcriptomics of mouse and human adipose tissue and their implications for the field, both for discovery and for therapy.
Collapse
|
|
34
|
Kim KJ, Jeong ES, Lee KH, Na JR, Park S, Kim JS, Na CS, Kim YR, Kim S. Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Promotes Lipolysis and Thermogenesis In Vitro and In Vivo. Molecules 2020; 25:molecules25245954. [PMID: 33339214 PMCID: PMC7766442 DOI: 10.3390/molecules25245954] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 02/06/2023] Open
Abstract
Previously, we demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) and ellagic acid has hypocholesterolemic and antiobesity activity, at least partially mediated by the downregulation of adipogenic and lipogenic gene expression in high-fat diet (HFD)-fed animals. The present study investigated the thermogenic and lipolytic antiobesity effects of 5-uRCK and ellagic acid in HFD-induced obese C57BL/6 mice and explored its mechanism of action. Mice fed an HFD received 5-uRCK or ellagic acid as a post-treatment or pretreatment. Both post-treated and pretreated mice showed significant reductions in body weight and adipose tissue mass compared to the HFD-fed mice. The protein levels of lipolysis-associated proteins, such as adipose triglyceride lipase (ATGL), phosphorylated hormone-sensitive lipase (p-HSL), and perilipin1 (PLIN1), were significantly increased in both the 5-uRCK- and ellagic acid-treated mouse epididymal white adipose tissue (eWAT). Additionally, thermogenesis-associated proteins, such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl transferase-1 (CPT1), uncoupling protein 1 (UCP1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), in inguinal white adipose tissue (ingWAT) were clearly increased in both the 5-uRCK- and ellagic acid-treated mice compared to HFD-fed mice. These results suggest that 5-uRCK and ellagic acid are effective for suppressing body weight gain and enhancing the lipid profile.
Collapse
Affiliation(s)
- Kyeong Jo Kim
- Central R&D Center, Bioresources and Technology (B&Tech) Co., Ltd., Gwangju 61239, Korea; (K.J.K.); (E.-S.J.); (K.H.L.); (J.-R.N.); (S.P.); (J.S.K.)
- College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Korea
| | - Eui-Seon Jeong
- Central R&D Center, Bioresources and Technology (B&Tech) Co., Ltd., Gwangju 61239, Korea; (K.J.K.); (E.-S.J.); (K.H.L.); (J.-R.N.); (S.P.); (J.S.K.)
| | - Ki Hoon Lee
- Central R&D Center, Bioresources and Technology (B&Tech) Co., Ltd., Gwangju 61239, Korea; (K.J.K.); (E.-S.J.); (K.H.L.); (J.-R.N.); (S.P.); (J.S.K.)
| | - Ju-Ryun Na
- Central R&D Center, Bioresources and Technology (B&Tech) Co., Ltd., Gwangju 61239, Korea; (K.J.K.); (E.-S.J.); (K.H.L.); (J.-R.N.); (S.P.); (J.S.K.)
| | - Soyi Park
- Central R&D Center, Bioresources and Technology (B&Tech) Co., Ltd., Gwangju 61239, Korea; (K.J.K.); (E.-S.J.); (K.H.L.); (J.-R.N.); (S.P.); (J.S.K.)
| | - Jin Seok Kim
- Central R&D Center, Bioresources and Technology (B&Tech) Co., Ltd., Gwangju 61239, Korea; (K.J.K.); (E.-S.J.); (K.H.L.); (J.-R.N.); (S.P.); (J.S.K.)
| | - Chang-Su Na
- College of Korean Medicine, Dongshin University, Naju-si, Jeollanam-do 58245, Korea;
| | - Young Ran Kim
- College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Korea
- Correspondence: (Y.R.K.); (S.K.); Tel.: +82-(62)-528-2201 (S.K.); Fax: +82-(62)-528-2202 (S.K.)
| | - Sunoh Kim
- Central R&D Center, Bioresources and Technology (B&Tech) Co., Ltd., Gwangju 61239, Korea; (K.J.K.); (E.-S.J.); (K.H.L.); (J.-R.N.); (S.P.); (J.S.K.)
- Correspondence: (Y.R.K.); (S.K.); Tel.: +82-(62)-528-2201 (S.K.); Fax: +82-(62)-528-2202 (S.K.)
| |
Collapse
|
|
35
|
Abstract
Obesity has become a worldwide issue and is accompanied by serious complications. Western high energy diet has been identified to be a major factor contributing to the current obesity pandemic. Thus, it is important to optimize dietary composition, bioactive substances, and agents to prevent and treat obesity. To date, extracts from plants, such as vegetables, tea, fruits, and Chinese herbal medicine, have been showed to have the abilities of regulating adipogenesis and attenuating obesity. These plant extracts mainly contain polyphenols, alkaloids, and terpenoids, which could play a significant role in anti-obesity through various signaling pathways and gut microbiota. Those reported anti-obesity mechanisms mainly include inhibiting white adipose tissue growth and lipogenesis, promoting lipolysis, brown/beige adipose tissue development, and muscle thermogenesis. In this review, we summarize the plant extracts and their possible mechanisms responsible for their anti-obesity effects. Based on the current findings, dietary plant extracts and foods containing these bioactive compounds can be potential preventive or therapeutic agents for obesity and its related metabolic diseases.
Collapse
Affiliation(s)
- Han-Ning Wang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Jin-Zhu Xiang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Zhi Qi
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Min Du
- Department of Animal Sciences, Washington State University, Pullman, Washington, USA
| |
Collapse
|
|
36
|
Mendes C, Gomes G, Belpiede LT, do Carmo Buonfiglio D, Motta-Teixeira LC, Amaral FG, Cipolla-Neto J. The effects of melatonin daily supplementation to aged rats on the ability to withstand cold, thermoregulation and body weight. Life Sci 2020; 265:118769. [PMID: 33309717 DOI: 10.1016/j.lfs.2020.118769] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/05/2020] [Accepted: 11/13/2020] [Indexed: 02/01/2023]
Abstract
AIMS Investigate the role of melatonin on the regulation of body temperature in aged animals that have impaired melatonin production. MATERIAL AND METHODS Aged Male Wistar rats were randomly assigned to the following groups: 1) control (vehicle added to the water bottles during the dark phase) and 2) melatonin-treated (10 mg/kg melatonin added to the water bottles during the dark phase). Before and after 16 weeks of vehicle or melatonin treatment, control group and melatonin-treated animals were acutely exposed to 18 °C for 2 h for an acute cold challenge and thermal images were obtained using an infrared camera. After 16 weeks, animals were euthanized and brown and beige adipocytes were collected for analysis of genes involved in the thermogenesis process by real-time PCR, and the uncoupling protein expression was evaluated by immunoblotting. Browning intensity of beige adipocytes were quantified by staining with hematoxylin-eosin. KEY FINDINGS Chronic melatonin supplementation induced a minor increase in body mass and increased the animal's thermogenic potential in the cold acute challenge. Brown and beige adipocytes acted in a coordinated and complementary way to ensure adequate heat production. SIGNIFICANCE Melatonin plays an important role in the thermoregulatory mechanisms, ensuring greater capacity to withstand cold and, also, participating in the regulation of energy balance.
Collapse
Affiliation(s)
- Caroline Mendes
- Neurobiology Lab, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Guilherme Gomes
- Department of Physics and Interdisciplinary Science (FCI), São Carlos Institute of Physics (IFSC), University of São Paulo, São Paulo, Brazil
| | - Luciana Tocci Belpiede
- Neurobiology Lab, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | | | - Lívia Clemente Motta-Teixeira
- Neurobiology Lab, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Fernanda Gaspar Amaral
- Pineal Neurobiology Lab, Department of Physiology, Federal University of São Paulo, São Paulo, SP, Brazil
| | - José Cipolla-Neto
- Neurobiology Lab, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
| |
Collapse
|
|
37
|
Lizcano F, Arroyave F. Control of Adipose Cell Browning and Its Therapeutic Potential. Metabolites 2020; 10:metabo10110471. [PMID: 33227979 PMCID: PMC7699191 DOI: 10.3390/metabo10110471] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/20/2020] [Accepted: 11/02/2020] [Indexed: 12/20/2022] Open
Abstract
Adipose tissue is the largest endocrine organ in humans and has an important influence on many physiological processes throughout life. An increasing number of studies have described the different phenotypic characteristics of fat cells in adults. Perhaps one of the most important properties of fat cells is their ability to adapt to different environmental and nutritional conditions. Hypothalamic neural circuits receive peripheral signals from temperature, physical activity or nutrients and stimulate the metabolism of white fat cells. During this process, changes in lipid inclusion occur, and the number of mitochondria increases, giving these cells functional properties similar to those of brown fat cells. Recently, beige fat cells have been studied for their potential role in the regulation of obesity and insulin resistance. In this context, it is important to understand the embryonic origin of beige adipocytes, the response of adipocyte to environmental changes or modifications within the body and their ability to transdifferentiate to elucidate the roles of these cells for their potential use in therapeutic strategies for obesity and metabolic diseases. In this review, we discuss the origins of the different fat cells and the possible therapeutic properties of beige fat cells.
Collapse
Affiliation(s)
- Fernando Lizcano
- Center of Biomedical Investigation, (CIBUS), Universidad de La Sabana, 250008 Chia, Colombia
- Correspondence:
| | - Felipe Arroyave
- Doctoral Program in Biociencias, Universidad de La Sabana, 250008 Chia, Colombia
| |
Collapse
|
|
38
|
Gharanei S, Shabir K, Brown JE, Weickert MO, Barber TM, Kyrou I, Randeva HS. Regulatory microRNAs in Brown, Brite and White Adipose Tissue. Cells 2020; 9:cells9112489. [PMID: 33207733 PMCID: PMC7696849 DOI: 10.3390/cells9112489] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/02/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) constitute a class of short noncoding RNAs which regulate gene expression by targeting messenger RNA, inducing translational repression and messenger RNA degradation. This regulation of gene expression by miRNAs in adipose tissue (AT) can impact on the regulation of metabolism and energy homeostasis, particularly considering the different types of adipocytes which exist in mammals, i.e., white adipocytes (white AT; WAT), brown adipocytes (brown AT; BAT), and inducible brown adipocytes in WAT (beige or brite or brown-in-white adipocytes). Indeed, an increasing number of miRNAs has been identified to regulate key signaling pathways of adipogenesis in BAT, brite AT, and WAT by acting on transcription factors that promote or inhibit adipocyte differentiation. For example, MiR-328, MiR-378, MiR-30b/c, MiR-455, MiR-32, and MiR-193b-365 activate brown adipogenesis, whereas MiR-34a, MiR-133, MiR-155, and MiR-27b are brown adipogenesis inhibitors. Given that WAT mainly stores energy as lipids, whilst BAT mainly dissipates energy as heat, clarifying the effects of miRNAs in different types of AT has recently attracted significant research interest, aiming to also develop novel miRNA-based therapies against obesity, diabetes, and other obesity-related diseases. Therefore, this review presents an up-to-date comprehensive overview of the role of key regulatory miRNAs in BAT, brite AT, and WAT.
Collapse
Affiliation(s)
- Seley Gharanei
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Kiran Shabir
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
| | - James E. Brown
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
| | - Martin O. Weickert
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Centre of Applied Biological & Exercise Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
| | - Thomas M. Barber
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
- Correspondence:
| |
Collapse
|
|
39
|
Svoboda LK, Neier K, Wang K, Cavalcante RG, Rygiel CA, Tsai Z, Jones TR, Liu S, Goodrich JM, Lalancette C, Colacino JA, Sartor MA, Dolinoy DC. Tissue and sex-specific programming of DNA methylation by perinatal lead exposure: implications for environmental epigenetics studies. Epigenetics 2020; 16:1102-1122. [PMID: 33164632 DOI: 10.1080/15592294.2020.1841872] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Early developmental environment can influence long-term health through reprogramming of the epigenome. Human environmental epigenetics studies rely on surrogate tissues, such as blood, to assess the effects of environment on disease-relevant but inaccessible target tissues. However, the extent to which environment-induced epigenetic changes are conserved between these tissues is unclear. A better understanding of this conservation is imperative for effective design and interpretation of human environmental epigenetics studies. The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium was established by the National Institute of Environmental Health Sciences to address the utility of surrogate tissues as proxies for toxicant-induced epigenetic changes in target tissues. We and others have recently reported that perinatal exposure to lead (Pb) is associated with adverse metabolic outcomes. Here, we investigated the sex-specific effects of perinatal exposure to a human environmentally relevant level of Pb on DNA methylation in paired liver and blood samples from adult mice using enhanced reduced-representation bisulphite sequencing. Although Pb exposure ceased at 3 weeks of age, we observed thousands of sex-specific differentially methylated cytosines in the blood and liver of Pb-exposed animals at 5 months of age, including 44 genomically imprinted loci. We observed significant tissue overlap in the genes mapping to differentially methylated cytosines. A small but significant subset of Pb-altered genes exhibit basal sex differences in gene expression in the mouse liver. Collectively, these data identify potential molecular targets for Pb-induced metabolic diseases, and inform the design of more robust human environmental epigenomics studies.
Collapse
Affiliation(s)
- Laurie K Svoboda
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Kari Neier
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Kai Wang
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School Palmer Commons, Ann Arbor, MI, USA
| | | | - Christine A Rygiel
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Zing Tsai
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.,Department of Computational Medicine and Bioinformatics, University of Michigan Medical School Palmer Commons, Ann Arbor, MI, USA
| | - Tamara R Jones
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Siyu Liu
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School Palmer Commons, Ann Arbor, MI, USA
| | - Jaclyn M Goodrich
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Claudia Lalancette
- Epigenomics Core, University of Michigan, Medical School, Ann Arbor, MI, USA
| | - Justin A Colacino
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.,Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Maureen A Sartor
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School Palmer Commons, Ann Arbor, MI, USA.,Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA
| | - Dana C Dolinoy
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.,Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| |
Collapse
|
|
40
|
Sharma G, Hu C, Staquicini DI, Brigman JL, Liu M, Mauvais-Jarvis F, Pasqualini R, Arap W, Arterburn JB, Hathaway HJ, Prossnitz ER. Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes. Sci Transl Med 2020; 12:12/528/eaau5956. [PMID: 31996464 DOI: 10.1126/scitranslmed.aau5956] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 07/23/2019] [Accepted: 12/30/2019] [Indexed: 12/12/2022]
Abstract
Human obesity has become a global health epidemic, with few safe and effective pharmacological therapies currently available. The systemic loss of ovarian estradiol (E2) in women after menopause greatly increases the risk of obesity and metabolic dysfunction, revealing the critical role of E2 in this setting. The salutary effects of E2 are traditionally attributed to the classical estrogen receptors ERα and ERβ, with the contribution of the G protein-coupled estrogen receptor (GPER) still largely unknown. Here, we used ovariectomy- and diet-induced obesity (DIO) mouse models to evaluate the preclinical activity of GPER-selective small-molecule agonist G-1 (also called Tespria) against obesity and metabolic dysfunction. G-1 treatment of ovariectomized female mice (a model of postmenopausal obesity) reduced body weight and improved glucose homeostasis without changes in food intake, fuel source usage, or locomotor activity. G-1-treated female mice also exhibited increased energy expenditure, lower body fat content, and reduced fasting cholesterol, glucose, insulin, and inflammatory markers but did not display feminizing effects on the uterus (imbibition) or beneficial effects on bone health. G-1 treatment of DIO male mice did not elicit weight loss but prevented further weight gain and improved glucose tolerance, indicating that G-1 improved glucose homeostasis independently of its antiobesity effects. However, in ovariectomized DIO female mice, G-1 continued to elicit weight loss, reflecting possible sex differences in the mechanisms of G-1 action. In conclusion, this work demonstrates that GPER-selective agonism is a viable therapeutic approach against obesity, diabetes, and associated metabolic abnormalities in multiple preclinical male and female models.
Collapse
Affiliation(s)
- Geetanjali Sharma
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA
| | - Chelin Hu
- Department of Cell Biology and Physiology, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA
| | - Daniela I Staquicini
- Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.,Rutgers Cancer Institute of New Jersey, Newark, NJ 07103, USA
| | - Jonathan L Brigman
- Department of Neurosciences, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.,Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA
| | - Franck Mauvais-Jarvis
- Diabetes Discovery and Sex-Based Medicine Laboratory, Section of Endocrinology and Metabolism, Department of Medicine, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA.,Section of Endocrinology, Southeast Louisiana Veterans Administration Health Care System, New Orleans, LA 70112, USA
| | - Renata Pasqualini
- Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.,Rutgers Cancer Institute of New Jersey, Newark, NJ 07103, USA
| | - Wadih Arap
- Rutgers Cancer Institute of New Jersey, Newark, NJ 07103, USA.,Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Jeffrey B Arterburn
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, 88003, USA
| | - Helen J Hathaway
- Department of Cell Biology and Physiology, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.,University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA
| | - Eric R Prossnitz
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA. .,Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.,University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA
| |
Collapse
|
|
41
|
Zhao Q, Zhang Z, Rong W, Jin W, Yan L, Jin W, Xu Y, Cui X, Tang QQ, Pan D. KMT5c modulates adipocyte thermogenesis by regulating Trp53 expression. Proc Natl Acad Sci U S A 2020; 117:22413-22422. [PMID: 32839323 PMCID: PMC7486735 DOI: 10.1073/pnas.1922548117] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Brown and beige adipocytes harbor the thermogenic capacity to adapt to environmental thermal or nutritional changes. Histone methylation is an essential epigenetic modification involved in the modulation of nonshivering thermogenesis in adipocytes. Here, we describe a molecular network leading by KMT5c, a H4K20 methyltransferase, that regulates adipocyte thermogenesis and systemic energy expenditure. The expression of Kmt5c is dramatically induced by a β3-adrenergic signaling cascade in both brown and beige fat cells. Depleting Kmt5c in adipocytes in vivo leads to a decreased expression of thermogenic genes in both brown and subcutaneous (s.c.) fat tissues. These mice are prone to high-fat-diet-induced obesity and develop glucose intolerance. Enhanced transformation related protein 53 (Trp53) expression in Kmt5c knockout (KO) mice, that is due to the decreased repressive mark H4K20me3 on its proximal promoter, is responsible for the metabolic phenotypes. Together, these findings reveal the physiological role for KMT5c-mediated H4K20 methylation in the maintenance and activation of the thermogenic program in adipocytes.
Collapse
Affiliation(s)
- Qingwen Zhao
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, 200032 Shanghai, People's Republic of China
| | - Zhe Zhang
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, 200032 Shanghai, People's Republic of China
| | - Weiqiong Rong
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, 200032 Shanghai, People's Republic of China
| | - Weiwei Jin
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, 200032 Shanghai, People's Republic of China
| | - Linyu Yan
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, 200032 Shanghai, People's Republic of China
| | - Wenfang Jin
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, 200032 Shanghai, People's Republic of China
| | - Yingjiang Xu
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, 200032 Shanghai, People's Republic of China
| | - Xuan Cui
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, 200032 Shanghai, People's Republic of China
| | - Qi-Qun Tang
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, 200032 Shanghai, People's Republic of China
| | - Dongning Pan
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, 200032 Shanghai, People's Republic of China
| |
Collapse
|
|
42
|
Deng X, Li Y, Gu S, Chen Y, Yu B, Su J, Sun L, Liu Y. p53 Affects PGC1α Stability Through AKT/GSK-3β to Enhance Cisplatin Sensitivity in Non-Small Cell Lung Cancer. Front Oncol 2020; 10:1252. [PMID: 32974127 PMCID: PMC7471661 DOI: 10.3389/fonc.2020.01252] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/17/2020] [Indexed: 12/12/2022] Open
Abstract
Drug resistance greatly limits the therapeutic efficacy of treatment of non-small cell lung cancer (NSCLC). One of the important factors is the dysfunction of tumor suppressor p53. Recent studies have suggested that p53 suppresses tumors by regulating number of mitochondrial proteins, including peroxisome proliferator-activated receptor coactivator (PGC1α). Although several studies have confirmed the interaction between p53 and PGC1α, the precise mechanism has not been completely determined in NSCLC. In this study, we investigated the specific signaling between p53 and PGC1α to improve anti-tumor drug effects on NSCLC. We found that low expression of p53 and high expression of PGC1α correlated with shorter survival time of NSCLC patients. In vitro experiments confirmed that NCI-H1299 (p53-null) cells had high levels of PGC1α and were insensitive to cisplatin (CDDP). When PGC1α was knocked down, the sensitivity to cisplatin was increased. Notably, the stability of PGC1α is an important mechanism in its activity regulation. We demonstrated that p53 decreased the stability of PGC1α via the ubiquitin proteasome pathway, which was mediated by protein kinase B (AKT) inhibition and glycogen synthase kinase (GSK-3β) activation. Therefore, p53 may regulate the stability of PGC1α through the AKT/GSK-3β pathway, thus affect the chemosensitivity of NSCLC.
Collapse
Affiliation(s)
- Xinyue Deng
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yang Li
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Shuang Gu
- Department of Thoracic Surgery, Jilin Provincial People's Hospital, Changchun, China
| | - Yingying Chen
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Bingbing Yu
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Jing Su
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Liankun Sun
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yanan Liu
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| |
Collapse
|
|
43
|
Zhu K, Mao G, Wu D, Yu C, Cheng H, Xiao H, Ye X, Linhardt RJ, Orfila C, Chen S. Highly Branched RG-I Domain Enrichment Is Indispensable for Pectin Mitigating against High-Fat Diet-Induced Obesity. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:8688-8701. [PMID: 32633953 DOI: 10.1021/acs.jafc.0c02654] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Obesity is associated with gut microbiome dysbiosis. Our previous research has shown that highly branched rhamnogalacturonan type I (RG-I)-enriched pectin (WRP, 531.5 kDa, 70.44% RG-I, Rha/(Gal + Ara) = 20) and its oligosaccharide with less branched RG-I [DWRP, 12.1 kDa, 50.29% RG-I, Rha/(Gal + Ara) = 6] are potential prebiotics. The present study is conducted to uncover the impact of the content, molecular size, and branch degrees of RG-I on the inhibiting effect of high-fat diet (HFD)-induced obesity. The commercial pectin (CP, 496.2 kDa, 35.77% RG-I, Rha/(Gal + Ara) = 6), WRP, and DWRP were orally administered to HFD-fed C57BL/6J mice (100 mg kg-1 d-1) to determine their individual effects on obesity. WRP significantly prevented bodyweight gain, insulin resistance, and inflammatory responses in HFD-fed mice. No obvious anti-obesity effect was observed in either CP or DWRP supplementation. A mechanistic study revealed that CP and DWRP could not enhance the diversity of gut microbiota, while WRP treatment positively modulated the gut microbiota of obese mice by increasing the abundance of Butyrivibrio, Roseburia, Barnesiella, Flavonifractor, Acetivibrio, and Clostridium cluster IV. Furthermore, WRP significantly promoted browning of white adipose tissues in HFD-fed mice, while CP and DWRP did not. WRP can attenuate the HFD-induced obesity by modulation of gut microbiota and lipid metabolism. Highly branched RG-I domain enrichment is essential for pectin mitigating against the HFD-induced obesity.
Collapse
Affiliation(s)
- Kai Zhu
- College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, Zhejiang University, Hangzhou 310058, China
| | - Guizhu Mao
- College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, Zhejiang University, Hangzhou 310058, China
| | - Dongmei Wu
- College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, Zhejiang University, Hangzhou 310058, China
| | - Chengxiao Yu
- College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, Zhejiang University, Hangzhou 310058, China
| | - Huan Cheng
- College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, Zhejiang University, Hangzhou 310058, China
- Fuli Institute of Food Science, Zhejiang University, Hangzhou 310058, China
- Ningbo Research Institute, Zhejiang University, Ningbo 315100, China
| | - Hang Xiao
- College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, Zhejiang University, Hangzhou 310058, China
- Department of Food Science, University of Massachusetts, Amherst, Massachusetts 01003, United States
| | - Xingqian Ye
- College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, Zhejiang University, Hangzhou 310058, China
- Fuli Institute of Food Science, Zhejiang University, Hangzhou 310058, China
- Ningbo Research Institute, Zhejiang University, Ningbo 315100, China
| | - Robert J Linhardt
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, United States
| | - Caroline Orfila
- School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, U.K
| | - Shiguo Chen
- College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, Zhejiang University, Hangzhou 310058, China
- Fuli Institute of Food Science, Zhejiang University, Hangzhou 310058, China
- Ningbo Research Institute, Zhejiang University, Ningbo 315100, China
| |
Collapse
|
|
44
|
Maurer S, Harms M, Boucher J. The colorful versatility of adipocytes: white-to-brown transdifferentiation and its therapeutic potential in humans. FEBS J 2020; 288:3628-3646. [PMID: 32621398 DOI: 10.1111/febs.15470] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/17/2020] [Accepted: 06/29/2020] [Indexed: 12/22/2022]
Abstract
Brown and brite adipocytes contribute to energy expenditure through nonshivering thermogenesis. Though these cell types are thought to arise primarily from the de novo differentiation of precursor cells, their abundance is also controlled through the transdifferentiation of mature white adipocytes. Here, we review recent advances in our understanding of the regulation of white-to-brown transdifferentiation, as well as the conversion of brown and brite adipocytes to dormant, white-like fat cells. Converting mature white adipocytes into brite cells or reactivating dormant brown and brite adipocytes has emerged as a strategy to ameliorate human metabolic disorders. We analyze the evidence of learning from mice and how they translate to humans to ultimately scrutinize the relevance of this concept. Moreover, we estimate that converting a small percentage of existing white fat mass in obese subjects into active brite adipocytes could be sufficient to achieve meaningful benefits in metabolism. In conclusion, novel browning agents have to be identified before adipocyte transdifferentiation can be realized as a safe and efficacious therapy.
Collapse
Affiliation(s)
- Stefanie Maurer
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Matthew Harms
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Jeremie Boucher
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.,Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
|
45
|
The Gintonin-Enriched Fraction of Ginseng Regulates Lipid Metabolism and Browning via the cAMP-Protein Kinase a Signaling Pathway in Mice White Adipocytes. Biomolecules 2020; 10:biom10071048. [PMID: 32679738 PMCID: PMC7407952 DOI: 10.3390/biom10071048] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/05/2020] [Accepted: 07/13/2020] [Indexed: 12/20/2022] Open
Abstract
Obesity is a major health concern and is becoming an increasingly serious societal problem worldwide. The browning of white adipocytes has received considerable attention because of its potential protective effect against obesity-related metabolic disease. The gintonin-enriched fraction (GEF) is a non-saponin, glycolipoprotein component of ginseng that is known to have neuroprotective and anti-inflammatory effects. However, the anti-obesity and browning effects of GEF have not been explored to date. Therefore, we aimed to determine whether GEF has a preventive effect against obesity. We differentiated 3T3-L1 cells and mouse primary subcutaneous adipocytes for 8 days in the presence or absence of GEF, and then measured the expression of intermediates in signaling pathways that regulate triglyceride (TG) synthesis and browning by Western blotting and immunofluorescence analysis. We found that GEF reduced lipid accumulation by reducing the expression of pro-adipogenic and lipogenic factors, and increased lipolysis and thermogenesis, which may be mediated by an increase in the phosphorylation of protein kinase A. These findings suggest that GEF may induce fat metabolism and energy expenditure in white adipocytes and therefore may represent a potential treatment for obesity.
Collapse
|
|
46
|
Mangiferin induces the expression of a thermogenic signature via AMPK signaling during brown-adipocyte differentiation. Food Chem Toxicol 2020; 141:111415. [PMID: 32417366 DOI: 10.1016/j.fct.2020.111415] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/17/2020] [Accepted: 05/04/2020] [Indexed: 02/08/2023]
Abstract
Mangiferin (MF) from Mangifera indica has been serendipitously found to ameliorate obesity and is used as an antioxidant, anti-inflammatory, antimicrobial, and anticancer agent. Nonetheless, the mechanism of MF-induced brown-adipose-tissue activation has not been studied. Therefore, we investigated the effect of MF on thermogenic features during brown-adipocyte differentiation. Treatment with MF improved the expression of a brown-fat signature and of mitochondrial-mass-related genes, thus resulting in UCP1 induction. MF also raised the expression of other thermogenic regulators, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), PR domain-containing protein 16 (PRDM16), and peroxisome proliferator-activated receptors alpha and gamma (PPAR-α and -γ). MF promoted mitochondrial biogenesis, judging by increased expression of cell death-inducing DNA fragmentation factor α-like effector A (CIDEA), mitochondrial transcription factor A (TFAM), iodothyronine deiodinase 2 (DIO2), cytochrome c oxidase subunit 7A (COX7A), cyclooxygenase 2 (COX2), sirtuin 1 (SIRT1), and nuclear respiratory factor 1 (NRF1). MF treatment increased the mitochondrial DNA amount and improved mitochondrial respiratory function by increasing the oxygen consumption rate during brown-adipocyte differentiation. A gene knockdown assay involving small interfering RNA and competitive inhibition with dorsomorphin revealed that MF may promote thermogenesis in brown preadipocytes via activation of AMPK signaling. Collectively, our findings suggest that MF may be a novel pharmaceutical agent that can ameliorate obesity via activation of brown adipose tissue.
Collapse
|
|
47
|
Gordon DM, Neifer KL, Hamoud ARA, Hawk CF, Nestor-Kalinoski AL, Miruzzi SA, Morran MP, Adeosun SO, Sarver JG, Erhardt PW, McCullumsmith RE, Stec DE, Hinds TD. Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator-activated receptor α. J Biol Chem 2020; 295:9804-9822. [PMID: 32404366 DOI: 10.1074/jbc.ra120.013700] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/11/2020] [Indexed: 12/18/2022] Open
Abstract
Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator-activated receptor α (PPARα). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARα target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor β 3 (Adrb3). We also found that bilirubin is a selective ligand for PPARα and does not affect the activities of the related proteins PPARγ and PPARδ. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPARα-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARα coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.
Collapse
Affiliation(s)
- Darren M Gordon
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.,Center for Diabetes and Endocrine Research (CeDER), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Kari L Neifer
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Abdul-Rizaq Ali Hamoud
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Charles F Hawk
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Andrea L Nestor-Kalinoski
- Advanced Microscopy and Imaging Center, Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Scott A Miruzzi
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Michael P Morran
- Advanced Microscopy and Imaging Center, Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Samuel O Adeosun
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Jeffrey G Sarver
- Center for Drug Design and Development (CD3), Department of Pharmacology and Experimental Therapeutics, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, Ohio, USA
| | - Paul W Erhardt
- Center for Drug Design and Development (CD3), Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, Ohio, USA
| | - Robert E McCullumsmith
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.,ProMedica, Toledo, Ohio, USA
| | - David E Stec
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Terry D Hinds
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA .,Center for Diabetes and Endocrine Research (CeDER), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| |
Collapse
|
|
48
|
Ahmad B, Serpell CJ, Fong IL, Wong EH. Molecular Mechanisms of Adipogenesis: The Anti-adipogenic Role of AMP-Activated Protein Kinase. Front Mol Biosci 2020; 7:76. [PMID: 32457917 PMCID: PMC7226927 DOI: 10.3389/fmolb.2020.00076] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/03/2020] [Indexed: 12/24/2022] Open
Abstract
Obesity is now a widespread disorder, and its prevalence has become a critical concern worldwide, due to its association with common co-morbidities like cancer, cardiovascular diseases and diabetes. Adipose tissue is an endocrine organ and therefore plays a critical role in the survival of an individual, but its dysfunction or excess is directly linked to obesity. The journey from multipotent mesenchymal stem cells to the formation of mature adipocytes is a well-orchestrated program which requires the expression of several genes, their transcriptional factors, and signaling intermediates from numerous pathways. Understanding all the intricacies of adipogenesis is vital if we are to counter the current epidemic of obesity because the limited understanding of these intricacies is the main barrier to the development of potent therapeutic strategies against obesity. In particular, AMP-Activated Protein Kinase (AMPK) plays a crucial role in regulating adipogenesis – it is arguably the central cellular energy regulation protein of the body. Since AMPK promotes the development of brown adipose tissue over that of white adipose tissue, special attention has been given to its role in adipose tissue development in recent years. In this review, we describe the molecular mechanisms involved in adipogenesis, the role of signaling pathways and the substantial role of activated AMPK in the inhibition of adiposity, concluding with observations which will support the development of novel chemotherapies against obesity epidemics.
Collapse
Affiliation(s)
- Bilal Ahmad
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | | | - Isabel Lim Fong
- Department of Paraclinical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Kota Samarahan, Malaysia
| | - Eng Hwa Wong
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| |
Collapse
|
|
49
|
Liu S, Chang X, Yu J, Xu W. Cerasus humilis Cherry Polyphenol Reduces High-Fat Diet-Induced Obesity in C57BL/6 Mice by Mitigating Fat Deposition, Inflammation, and Oxidation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:4424-4436. [PMID: 32227855 DOI: 10.1021/acs.jafc.0c01617] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
This study aimed to determine the anti-obesity effects and mechanisms of Cerasus humilis polyphenol (CHP) in C57BL/6 obese mice and 3T3-L1 cells. High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used for the qualitative and quantitative identification of CHP components. The obese mice, induced by feeding high-fat diet (HFD), were treated with CHP (250 mg/kg/day) by gavage for 12 weeks. Orlistat was gavaged at 15.6 mg/kg bw/day, as a positive control group. The analysis revealed that the main components of CHP were procyanidin B2, cyanidin-3-glucoside, and pelargonidin-3-glucoside. CHP dietary supplementation significantly reduced body weight and improved blood lipid measurements in HFD-fed mice (p < 0.01). Moreover, it inhibited mRNA expression of miR-122, Srebp-1c, and Cpt1a (p < 0.01) and reduced hepatic lipid deposition, as seen by hematoxylin and eosin staining. CHP downregulated the protein expression of PPARγ and C/EBPα in HFD-induced obese mice and inhibited adipocyte differentiation (p < 0.01). Compared with the HFD group, CHP supplementation had an obvious anti-inflammatory effect (decreased protein expression, such as TNF-α, IL-6, and MCP1), reducing leptin levels and TNF-α secretion in serum and cells (p < 0.01). CHP significantly inhibited the expression of miR-27a/b (53.3 and 29.9%, p < 0.01) in mice retroperitoneal white adipocytes, enhancing the expression of the target gene Prdm16 and significantly upregulating Sirt1 (105.5%, p < 0.01) compared with the HFD group. Moreover, CHP supplementation effectively improved oxidative stress (ROS, T-AOC, SOD, CAT, and GSH-Px) induced by HFD in obese mice (p < 0.01). Thus, CHP mitigates adipocyte differentiation, browning of white adipocytes, and reduction of inflammation and antioxidant activity to reduce obesity. Consequently, these results provide novel insights into the anti-obesity roles of CHP in HFD-induced obesity.
Collapse
Affiliation(s)
- Suwen Liu
- College of Food Science & Technology, Hebei Normal University of Science and Technology, Qinhuangdao, Hebei 066004, China
| | - Xuedong Chang
- College of Food Science & Technology, Hebei Normal University of Science and Technology, Qinhuangdao, Hebei 066004, China
- Hebei Yanshan Special Industrial Technology Research Institute, Qinhuangdao, Hebei 066004, China
| | - Jincheng Yu
- College of Food Science & Technology, Hebei Normal University of Science and Technology, Qinhuangdao, Hebei 066004, China
| | - Weifeng Xu
- College of Food Science & Technology, Hebei Normal University of Science and Technology, Qinhuangdao, Hebei 066004, China
| |
Collapse
|
|
50
|
Kang HS, Lee JH, Oh KJ, Lee EW, Han BS, Park KY, Suh JM, Min JK, Chi SW, Lee SC, Bae KH, Kim WK. IDH1-dependent α-KG regulates brown fat differentiation and function by modulating histone methylation. Metabolism 2020; 105:154173. [PMID: 32035087 DOI: 10.1016/j.metabol.2020.154173] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/20/2020] [Accepted: 02/04/2020] [Indexed: 10/25/2022]
Abstract
OBJECTIVE Brown adipocytes play important roles in the regulation of energy homeostasis by uncoupling protein 1-mediated non-shivering thermogenesis. Recent studies suggest that brown adipocytes as novel therapeutic targets for combating obesity and associated diseases, such as type II diabetes. However, the molecular mechanisms underlying brown adipocyte differentiation and function are not fully understood. METHODS We employed previous findings obtained through proteomic studies performed to assess proteins displaying altered levels during brown adipocyte differentiation. Here, we performed assays to determine the functional significance of their altered levels during brown adipogenesis and development. RESULTS We identified isocitrate dehydrogenase 1 (IDH1) as upregulated during brown adipocyte differentiation, with subsequent investigations revealing that ectopic expression of IDH1 inhibited brown adipogenesis, whereas suppression of IDH1 levels promoted differentiation of brown adipocytes. Additionally, Idh1 overexpression resulted in increased levels of intracellular α-ketoglutarate (α-KG) and inhibited the expression of genes involved in brown adipogenesis. Exogenous treatment with α-KG reduced brown adipogenesis during the early phase of differentiation, and ChIP analysis revealed that IDH1-mediated α-KG reduced trimethylation of histone H3 lysine 4 in the promoters of genes associated with brown adipogenesis. Furthermore, administration of α-KG decreased adipogenic gene expression by modulating histone methylation in brown adipose tissues of mice. CONCLUSION These results suggested that the IDH1-α-KG axis plays an important role in regulating brown adipocyte differentiation and might represent a therapeutic target for treating metabolic diseases.
Collapse
Affiliation(s)
- Hyun Sup Kang
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea
| | - Jae Ho Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea
| | - Eun Woo Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
| | - Baek Soo Han
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea
| | - Kun-Young Park
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea
| | - Jae Myoung Suh
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea; Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Jeong-Ki Min
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea
| | - Seung-Wook Chi
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea
| | - Sang Chul Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea.
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea.
| |
Collapse
|