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Deng D, Xu L, Liu Y, Li C, Jiang Q, Shi J, Feng S, Lin Y. HIIT versus MICT in MASLD: mechanisms mediated by gut-liver axis crosstalk, mitochondrial dynamics remodeling, and adipokine signaling attenuation. Lipids Health Dis 2025; 24:144. [PMID: 40241065 PMCID: PMC12004573 DOI: 10.1186/s12944-025-02565-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 04/10/2025] [Indexed: 04/18/2025] Open
Abstract
OBJECTIVE Compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on metabolic dysfunction-associated steatotic liver disease (MASLD), focusing on the mechanisms by which these two exercise modalities influence gut microbiota structure, bile acid metabolism, and intestinal barrier function, as well as their regulatory roles in hepatic lipid synthesis and oxidative dynamics. Explore the synergistic effects of exercise-mediated mitochondrial fusion remodeling and leptin signaling, elucidate the causal relationship between gut-derived factors and hepatic metabolic reprogramming, and reveal the potential multi-scale and cross-organ dominant mechanisms of exercise, providing a theoretical basis for systematically comparing the effects of different exercise modalities. METHODS Thirty-two male rats were randomly divided into NFD (n = 8) and HFD (n = 24) groups and fed normal chow and high-fat chow, respectively. After eight weeks, the HFD group was randomly divided into three groups: (1) MICT-8; (2) HIIT-8; and (3) HFD-8. At the end of the experiment, blood, liver, ileum, and skeletal muscle samples were collected for analysis of the rats' baseline conditions, mitochondrial function, hepatic lipid metabolism, bile acid pathway and gut microbiota, and synthesis of analyses. RESULTS Both modes of exercise ameliorated metabolic dysregulation and attenuated pathological progression, insulin resistance, and liver fat accumulation in rats with MASLD. Furthermore, both interventions counteracted HFD-induced intestinal barrier dysfunction and restored gut-liver axis homeostasis. HIIT and MICT also upregulated bile acid-related gene expression modulated butyrate-producing bacterial taxa, and adjusted the abundance of butyrate-generating bacteria. CONCLUSION Both HIIT and MICT improved lipid metabolism in MASLD rats and the difference between the HIIT and MICT groups was not statistically significant. It is noteworthy that HIIT was more effective in improving mitochondrial function in MASLD than MICT (P < 0.001).
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Affiliation(s)
- Dongkun Deng
- College of Sports and Human Sciences, Graduate School, Harbin Sport University, Harbin, 150008, P.R. China
| | - Lin Xu
- College of Sports and Human Sciences, Graduate School, Harbin Sport University, Harbin, 150008, P.R. China.
| | - Yufei Liu
- College of Sports and Human Sciences, Graduate School, Harbin Sport University, Harbin, 150008, P.R. China.
| | - Chang Li
- College of Sports and Human Sciences, Graduate School, Harbin Sport University, Harbin, 150008, P.R. China
| | - Qingfeng Jiang
- College of Sports and Human Sciences, Graduate School, Harbin Sport University, Harbin, 150008, P.R. China
| | - Jiaming Shi
- College of Sports and Human Sciences, Graduate School, Harbin Sport University, Harbin, 150008, P.R. China
| | - Shuo Feng
- College of Sports and Human Sciences, Graduate School, Harbin Sport University, Harbin, 150008, P.R. China
| | - Yunhua Lin
- College of Sports and Human Sciences, Graduate School, Harbin Sport University, Harbin, 150008, P.R. China
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Perakakis N, Mantzoros CS. Evidence from clinical studies of leptin: current and future clinical applications in humans. Metabolism 2024; 161:156053. [PMID: 39490439 DOI: 10.1016/j.metabol.2024.156053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/24/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
Leptin has been established as the prototype adipose tissue secreted hormone and as a major regulator of several human physiology functions. Here, we are primarily reviewing the findings from studies in humans involving leptin administration. We are describing the metabolic, endocrine and immunologic effects of leptin replacement in conditions of leptin deficiency, such as short-term fasting in healthy individuals, relative energy deficiency in sports (REDS), congenital leptin deficiency (CLD), generalized (GL) and partial lipodystrophy (PL), HIV-associated lipodystrophy (HIV-L) and of leptin treatment in conditions of leptin excess (common obesity, type 2 diabetes, steatotic liver disease). We are comparing the results with the findings from preclinical models and present the main conclusions regarding the role of leptin in human physiology, pathophysiology and therapeutics. We conclude that, in conditions of energy deficiency, leptin substitution effectively reduces body weight and fat mass through reduction of appetite, it improves hypertriglyceridemia, insulin resistance and hepatic steatosis (especially in GL and PL), it restores neuroendocrine function (especially the gonadotropic axis), it regulates adaptive immune system cell populations and it improves bone health. On the contrary, leptin treatment in conditions of leptin excess, such as common obesity and type 2 diabetes, does not improve any metabolic abnormalities. Strategies to overcome leptin tolerance/resistance in obesity and type 2 diabetes have provided promising results in animal studies, which should though be tested in humans in randomized clinical trials.
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Affiliation(s)
- Nikolaos Perakakis
- Division of Metabolic and Vascular Medicine, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
| | - Christos S Mantzoros
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
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3
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Münzberg H, Heymsfield SB, Berthoud HR, Morrison CD. History and future of leptin: Discovery, regulation and signaling. Metabolism 2024; 161:156026. [PMID: 39245434 PMCID: PMC11570342 DOI: 10.1016/j.metabol.2024.156026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/27/2024] [Accepted: 09/04/2024] [Indexed: 09/10/2024]
Abstract
The cloning of leptin 30 years ago in 1994 was an important milestone in obesity research. Prior to the discovery of leptin, obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause severe obesity, and it is now recognized that obesity is caused mostly by a dysregulation of central neuronal circuits. Since the discovery of the leptin-deficient obese mouse (ob/ob) the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, we have learned much about leptin and its action in the central nervous system. The first hope that leptin would cure obesity was quickly dampened because humans with obesity have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint to understand how neuronal circuits control energy homeostasis. Our expanding understanding of leptin function, interconnection of leptin signaling with other systems and impact on distinct physiological functions continues to guide and improve the development of safe and effective interventions to treat metabolic illnesses. This review highlights past concepts and current emerging concepts of the hormone leptin, leptin receptor signaling pathways and central targets to mediate distinct physiological functions.
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Affiliation(s)
- Heike Münzberg
- Pennington Biomedical Research Center, LSU System, Baton Rouge, LA, United States of America.
| | - Steven B Heymsfield
- Pennington Biomedical Research Center, LSU System, Baton Rouge, LA, United States of America
| | - Hans-Rudolf Berthoud
- Pennington Biomedical Research Center, LSU System, Baton Rouge, LA, United States of America
| | - Christopher D Morrison
- Pennington Biomedical Research Center, LSU System, Baton Rouge, LA, United States of America
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Stefanakis K, Upadhyay J, Ramirez-Cisneros A, Patel N, Sahai A, Mantzoros CS. Leptin physiology and pathophysiology in energy homeostasis, immune function, neuroendocrine regulation and bone health. Metabolism 2024; 161:156056. [PMID: 39481533 DOI: 10.1016/j.metabol.2024.156056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 10/28/2024] [Accepted: 10/28/2024] [Indexed: 11/02/2024]
Abstract
Since its discovery and over the past thirty years, extensive research has significantly expanded our understanding of leptin and its diverse roles in human physiology, pathophysiology and therapeutics. A prototypical adipokine initially identified for its critical function in appetite regulation and energy homeostasis, leptin has been revealed to also exert profound effects on the hypothalamic-pituitary-gonadal, thyroid, adrenal and growth hormone axis, differentially between animals and humans, as well as in regulating immune function. Beyond these roles, leptin plays a pivotal role in significantly affecting bone health by promoting bone formation and regulating bone metabolism both directly and indirectly through its neuroendocrine actions. The diverse actions of leptin are particularly notable in leptin-deficient animal models and in conditions characterized by low circulating leptin levels, such as lipodystrophies and relative energy deficiency. Conversely, the effectiveness of leptin is attenuated in leptin-sufficient states, such as obesity and other high-adiposity conditions associated with hyperleptinemia and leptin tolerance. This review attempts to consolidate 30 years of leptin research with an emphasis on its physiology and pathophysiology in humans, including its promising therapeutic potential. We discuss preclinical and human studies describing the pathophysiology of energy deficiency across organ systems and the significant role of leptin in regulating neuroendocrine, immune, reproductive and bone health. We finally present past proof of concept clinical trials of leptin administration in leptin-deficient subjects that have demonstrated positive neuroendocrine, reproductive, and bone health outcomes, setting the stage for future phase IIb and III randomized clinical trials in these conditions.
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Affiliation(s)
- Konstantinos Stefanakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jagriti Upadhyay
- Department of Medicine, Lahey Hospital and Medical Center, Burlington, MA, USA
| | - Arantxa Ramirez-Cisneros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Nihar Patel
- Department of Medicine, Lahey Hospital and Medical Center, Burlington, MA, USA
| | - Akshat Sahai
- Vassar Brothers Medical Center, Poughkeepsie, NY, USA
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Medicine, Boston VA Healthcare System, Boston, MA, USA.
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Prieur X, Cao L. Precision medicine: toward restoring fat with gene therapy in inherited lipodystrophy. Gene Ther 2024; 31:560-562. [PMID: 39317737 DOI: 10.1038/s41434-024-00489-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/10/2024] [Accepted: 09/18/2024] [Indexed: 09/26/2024]
Affiliation(s)
- Xavier Prieur
- l'Institut du Thorax, INSERM, CNRS, Nantes Université, CHU Nantes, Nantes, France.
| | - Lei Cao
- Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH, USA.
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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Clarke GS, Page AJ, Eldeghaidy S. The gut-brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies. Pharmacol Res Perspect 2024; 12:e70027. [PMID: 39417406 PMCID: PMC11483575 DOI: 10.1002/prp2.70027] [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: 01/16/2024] [Revised: 09/02/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
The gut-brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut-brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake.
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Affiliation(s)
- Georgia S. Clarke
- School of BiomedicineThe University of AdelaideAdelaideSouth AustraliaAustralia
- Robinson Research InstituteThe University of AdelaideAdelaideSouth AustraliaAustralia
- Nutrition, Diabetes and Gut Health, Lifelong Health ThemeSouth Australian Health and Medical Research Institute, SAHMRIAdelaideSouth AustraliaAustralia
| | - Amanda J. Page
- School of BiomedicineThe University of AdelaideAdelaideSouth AustraliaAustralia
- Nutrition, Diabetes and Gut Health, Lifelong Health ThemeSouth Australian Health and Medical Research Institute, SAHMRIAdelaideSouth AustraliaAustralia
| | - Sally Eldeghaidy
- Division of Food, Nutrition and DieteticsSchool of Biosciences, University of NottinghamNottinghamUK
- Sir Peter Mansfield Imaging CentreSchool of Physics and Astronomy, University of NottinghamNottinghamUK
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Vigouroux C, Mosbah H, Vatier C. Leptin replacement therapy in the management of lipodystrophy syndromes. ANNALES D'ENDOCRINOLOGIE 2024; 85:201-204. [PMID: 38871500 DOI: 10.1016/j.ando.2024.05.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
Lipodystrophy syndromes are rare diseases of genetic or acquired origin, characterized by quantitative and qualitative defects in adipose tissue. The metabolic consequences of lipodystrophy syndromes, such as insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis, are frequently very difficult to treat, resulting in significant risks of acute and/or chronic complications and of decreased quality of life. The production of leptin by lipodystrophic adipose tissue is decreased, more severely in generalized forms of lipodystrophy, where adipose tissue is absent from almost all body fat depots, than in partial forms of the disease, where lipoatrophy affects only some parts of the body and can be associated with increased body fat in other anatomical regions. Several lines of evidence in preclinical and clinical models have shown that leptin replacement therapy could improve the metabolic complications of lipodystrophy syndromes. Metreleptin, a recombinant leptin analogue, was approved as an orphan drug to treat the metabolic complications of leptin deficiency in patients with generalized lipodystrophy in the USA or with either generalized or partial lipodystrophy in Japan and Europe. In this brief review, we will discuss the benefits and limitations of this therapy, and the new expectations arising from the recent development of a therapeutic monoclonal antibody able to activate the leptin receptor.
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Affiliation(s)
- Corinne Vigouroux
- Service d'endocrinologie, diabétologie et endocrinologie de la reproduction, centre national de référence des pathologies rares de l'insulino-secrétion et de l'insulino-sensibilité (PRISIS), hôpital Saint-Antoine, Assistance publique-Hôpitaux de Paris, Paris, France; Centre de recherche Saint-Antoine, institut hospitalo-universitaire de cardio-métabolisme et nutrition (ICAN), Sorbonne université, Inserm UMR_S 938, Paris, France.
| | - Héléna Mosbah
- Centre de recherche Saint-Antoine, institut hospitalo-universitaire de cardio-métabolisme et nutrition (ICAN), Sorbonne université, Inserm UMR_S 938, Paris, France; Service endocrinologie, diabétologie, nutrition, centre de compétence PRISIS, CHU La Milétrie, Poitiers, France; Université Paris Cité, ECEVE UMR 1123, Inserm, Paris, France
| | - Camille Vatier
- Service d'endocrinologie, diabétologie et endocrinologie de la reproduction, centre national de référence des pathologies rares de l'insulino-secrétion et de l'insulino-sensibilité (PRISIS), hôpital Saint-Antoine, Assistance publique-Hôpitaux de Paris, Paris, France; Centre de recherche Saint-Antoine, institut hospitalo-universitaire de cardio-métabolisme et nutrition (ICAN), Sorbonne université, Inserm UMR_S 938, Paris, France
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8
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Perez-Leighton C, Kerr B, Scherer PE, Baudrand R, Cortés V. The interplay between leptin, glucocorticoids, and GLP1 regulates food intake and feeding behaviour. Biol Rev Camb Philos Soc 2024; 99:653-674. [PMID: 38072002 DOI: 10.1111/brv.13039] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 11/21/2023] [Accepted: 12/01/2023] [Indexed: 05/09/2024]
Abstract
Nutritional, endocrine, and neurological signals converge in multiple brain centres to control feeding behaviour and food intake as part of the allostatic regulation of energy balance. Among the several neuroendocrine systems involved, the leptin, glucocorticoid, and glucagon-like peptide 1 (GLP1) systems have been extensively researched. Leptin is at the top hierarchical level since its complete absence is sufficient to trigger severe hyperphagia. Glucocorticoids are key regulators of the energy balance adaptation to stress and their sustained excess leads to excessive adiposity and metabolic perturbations. GLP1 participates in metabolic adaptation to food intake, regulating insulin secretion and satiety by parallel central and peripheral signalling systems. Herein, we review the brain and peripheral targets of these three hormone systems that integrate to regulate food intake, feeding behaviour, and metabolic homeostasis. We examine the functional relationships between leptin, glucocorticoids, and GLP1 at the central and peripheral levels, including the cross-regulation of their circulating levels and their cooperative or antagonistic actions at different brain centres. The pathophysiological roles of these neuroendocrine systems in dysregulated intake are explored in the two extremes of body adiposity - obesity and lipodystrophy - and eating behaviour disorders.
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Affiliation(s)
- Claudio Perez-Leighton
- Departmento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
| | - Bredford Kerr
- Centro de Biología Celular y Biomedicina-CEBICEM, Facultad de Medicina y Ciencia, Universidad San Sebastián, Carmen Sylva 2444, Providencia, Santiago, Chile
| | - Philipp E Scherer
- Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA
| | - René Baudrand
- Departmento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
- Centro Translacional de Endocrinología (CETREN), Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
| | - Víctor Cortés
- Departmento de Nutrición, Diabetes y Metabolismo, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
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9
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Bo T, Gao L, Yao Z, Shao S, Wang X, Proud CG, Zhao J. Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease. Cell Metab 2024; 36:947-968. [PMID: 38718757 DOI: 10.1016/j.cmet.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 01/22/2024] [Accepted: 04/09/2024] [Indexed: 06/26/2024]
Abstract
Insulin resistance (IR) is a major pathogenic factor in the progression of MASLD. In the liver, insulin suppresses gluconeogenesis and enhances de novo lipogenesis (DNL). During IR, there is a defect in insulin-mediated suppression of gluconeogenesis, but an unrestrained increase in hepatic lipogenesis persists. The mechanism of increased hepatic steatosis in IR is unclear and remains controversial. The key discrepancy is whether insulin retains its ability to directly regulate hepatic lipogenesis. Blocking insulin/IRS/AKT signaling reduces liver lipid deposition in IR, suggesting insulin can still regulate lipid metabolism; hepatic glucose metabolism that bypasses insulin's action may contribute to lipogenesis; and due to peripheral IR, other tissues are likely to impact liver lipid deposition. We here review the current understanding of insulin's action in governing different aspects of hepatic lipid metabolism under normal and IR states, with the purpose of highlighting the essential issues that remain unsettled.
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Affiliation(s)
- Tao Bo
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ling Gao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Zhenyu Yao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Shanshan Shao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Xuemin Wang
- Lifelong Health, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia
| | - Christopher G Proud
- Lifelong Health, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia.
| | - Jiajun Zhao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China.
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Meng Z, Liu C, Xu M, Tao Y, Li H, Wang X, Liao J, Wang M. Adipose transplantation improves metabolism and atherosclerosis but not perivascular adipose tissue abnormality or vascular dysfunction in lipodystrophic Seipin/Apoe null mice. Am J Physiol Cell Physiol 2024; 326:C1410-C1422. [PMID: 38525541 PMCID: PMC11371364 DOI: 10.1152/ajpcell.00698.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/14/2024] [Accepted: 03/21/2024] [Indexed: 03/26/2024]
Abstract
Adipose dysfunction in lipodystrophic SEIPIN deficiency is associated with multiple metabolic disorders and increased risks of developing cardiovascular diseases, such as atherosclerosis, cardiac hypertrophy, and heart failure. Recently, adipose transplantation has been found to correct adipose dysfunction and metabolic disorders in lipodystrophic Seipin knockout mice; however, whether adipose transplantation could improve lipodystrophy-associated cardiovascular consequences is still unclear. Here, we aimed to explore the effects of adipose transplantation on lipodystrophy-associated metabolic cardiovascular diseases in Seipin knockout mice crossed into atherosclerosis-prone apolipoprotein E (Apoe) knockout background. At 2 months of age, lipodystrophic Seipin/Apoe double knockout mice and nonlipodystrophic Apoe knockout controls were subjected to adipose transplantation or sham operation. Seven months later, mice were euthanized. Our data showed that although adipose transplantation had no significant impact on endogenous adipose atrophy or gene expression, it remarkably increased plasma leptin but not adiponectin concentration in Seipin/Apoe double knockout mice. This led to significantly reduced hyperlipidemia, hepatic steatosis, and insulin resistance in Seipin/Apoe double knockout mice. Consequently, atherosclerosis burden, intraplaque macrophage infiltration, and aortic inflammatory gene expression were all attenuated in Seipin/Apoe double knockout mice with adipose transplantation. However, adipocyte morphology, macrophage infiltration, or fibrosis of the perivascular adipose tissue was not altered in Seipin/Apoe double knockout mice with adipose transplantation, followed by no significant improvement of vasoconstriction or relaxation. In conclusion, we demonstrate that adipose transplantation could alleviate lipodystrophy-associated metabolic disorders and atherosclerosis but has an almost null impact on perivascular adipose abnormality or vascular dysfunction in lipodystrophic Seipin/Apoe double knockout mice.NEW & NOTEWORTHY Adipose transplantation (AT) reverses multiply metabolic derangements in lipodystrophy, but whether it could improve lipodystrophy-related cardiovascular consequences is unknown. Here, using Seipin/Apoe double knockout mice as a lipodystrophy disease model, we showed that AT partially restored adipose functionality, which translated into significantly reduced atherosclerosis. However, AT was incapable of reversing perivascular adipose abnormality or vascular dysfunction. The current study provides preliminary experimental evidence on the therapeutic potential of AT on lipodystrophy-related metabolic cardiovascular diseases.
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Affiliation(s)
- Zhe Meng
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Chuangxing Liu
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mengke Xu
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yongqiang Tao
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Haiyu Li
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xijia Wang
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jiawei Liao
- Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Mengyu Wang
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Choi S, Kang JG, Tran YTH, Jeong SH, Park KY, Shin H, Kim YH, Park M, Nahmgoong H, Seol T, Jeon H, Kim Y, Park S, Kim HJ, Kim MS, Li X, Bou Sleiman M, Lee E, Choi J, Eisenbarth D, Lee SH, Cho S, Moore DD, Auwerx J, Kim IY, Kim JB, Park JE, Lim DS, Suh JM. Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass. Nat Metab 2024; 6:847-860. [PMID: 38811804 PMCID: PMC11136666 DOI: 10.1038/s42255-024-01045-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 04/10/2024] [Indexed: 05/31/2024]
Abstract
Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.
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Affiliation(s)
- Sungwoo Choi
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
- National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Ju-Gyeong Kang
- National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Yen T H Tran
- National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Sun-Hye Jeong
- National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Kun-Young Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Hyemi Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Young Hoon Kim
- National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Myungsun Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Hahn Nahmgoong
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
| | - Taejun Seol
- National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Haeyon Jeon
- National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Yeongmin Kim
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences & Technology, Gachon University, Incheon, Republic of Korea
| | - Sanghee Park
- Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Hee-Joo Kim
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences & Technology, Gachon University, Incheon, Republic of Korea
| | - Min-Seob Kim
- Department of Fundamental Environment Research, Environmental Measurement and Analysis Center, National Institute of Environmental Research, Incheon, Republic of Korea
| | - Xiaoxu Li
- Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Maroun Bou Sleiman
- Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Eries Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Jinhyuk Choi
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - David Eisenbarth
- National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Sang Heon Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Suhyeon Cho
- National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - David D Moore
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA
| | - Johan Auwerx
- Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Il-Young Kim
- Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Jae Bum Kim
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
| | - Jong-Eun Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Dae-Sik Lim
- National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
| | - Jae Myoung Suh
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
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12
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Agarwal AK, Tunison K, Horton JD, Garg A. Regulated regeneration of adipose tissue in lipodystrophic Agpat2-null mice partially ameliorates hepatic steatosis. iScience 2024; 27:109517. [PMID: 38623324 PMCID: PMC11016861 DOI: 10.1016/j.isci.2024.109517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 01/22/2024] [Accepted: 03/14/2024] [Indexed: 04/17/2024] Open
Abstract
Both humans and mice with congenital generalized lipodystrophy due to AGPAT2 deficiency develop diabetes mellitus, insulin resistance, and hepatic steatosis, which have been attributed to the near total loss of adipose tissue (AT). Here, we show that regulated AT regeneration in doxycycline (dox)-fed Tg-AT-hAGPAT2;mAgpat2-/- mice partially ameliorates hepatic steatosis at 12 weeks of age and causes reduced expression of genes involved in hepatic de novo lipogenesis despite partial (∼30-50%) AT regeneration compared to that in wild-type mice. Compared to chow-fed Tg-AT-hAGPAT2;mAgpat2-/- mice, those fed dox diet had markedly reduced serum insulin levels, suggesting an improvement in insulin resistance. Interestingly, the fasting plasma glucose levels in dox-fed Tg-AT-hAGPAT2;mAgpat2-/- mice were no different than those in chow-fed wild-type mice. Indirect calorimetry revealed normalization in the energy balance of dox-fed Tg-AT-hAGPAT2;mAgpat2-/- mice compared to that in chow-fed mice. This study's findings suggest that partial AT regeneration in lipodystrophic mice can ameliorate metabolic derangements.
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Affiliation(s)
- Anil K. Agarwal
- Section of Nutrition and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Katie Tunison
- Section of Nutrition and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jay D. Horton
- Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Abhimanyu Garg
- Section of Nutrition and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USA
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13
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Paslawski R, Kowalczyk P, Paslawska U, Wiśniewski J, Dzięgiel P, Janiszewski A, Kiczak L, Zacharski M, Gawdzik B, Kramkowski K, Szuba A. Analysis of the Model of Atherosclerosis Formation in Pig Hearts as a Result of Impaired Activity of DNA Repair Enzymes. Int J Mol Sci 2024; 25:2282. [PMID: 38396961 PMCID: PMC10888614 DOI: 10.3390/ijms25042282] [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: 12/06/2023] [Revised: 02/05/2024] [Accepted: 02/11/2024] [Indexed: 02/25/2024] Open
Abstract
Excessive consumption of food rich in saturated fatty acids and carbohydrates can lead to metabolic disturbances and cardiovascular disease. Hyperlipidemia is a significant risk factor for acute cardiac events due to its association with oxidative stress. This leads to arterial wall remodeling, including an increase in the thickness of the intima media complex (IMT), and endothelial dysfunction leading to plaque formation. The decreased nitric oxide synthesis and accumulation of lipids in the wall result in a reduction in the vasodilating potential of the vessel. This study aimed to establish a clear relationship between markers of endothelial dysfunction and the activity of repair enzymes in cardiac tissue from a pig model of early atherosclerosis. The study was conducted on 28 female Polish Landrace pigs, weighing 40 kg (approximately 3.5 months old), which were divided into three groups. The control group (n = 11) was fed a standard, commercial, balanced diet (BDG) for 12 months. The second group (n = 9) was fed an unbalanced, high-calorie Western-type diet (UDG). The third group (n = 8) was fed a Western-type diet for nine months and then switched to a standard, balanced diet (regression group, RG). Control examinations, including blood and urine sampling, were conducted every three months under identical conditions with food restriction for 12 h and water restriction for four hours before general anesthesia. The study analyzed markers of oxidative stress formed during lipid peroxidation processes, including etheno DNA adducts, ADMA, and NEFA. These markers play a crucial role in reactive oxygen species analysis in ischemia-reperfusion and atherosclerosis in mammalian tissue. Essential genes involved in oxidative-stress-induced DNA demethylation like OGG1 (8-oxoguanine DNA glycosylase), MPG (N-Methylpurine DNA Glycosylase), TDG (Thymine-DNA glycosylase), APEX (apurinic/apirymidinic endodeoxyribonuclease 1), PTGS2 (prostaglandin-endoperoxide synthase 2), and ALOX (Arachidonate Lipoxygenase) were measured using the Real-Time RT-PCR method. The data suggest that high oxidative stress, as indicated by TBARS levels, is associated with high levels of DNA repair enzymes and depends on the expression of genes involved in the repair pathway. In all analyzed groups of heart tissue homogenates, the highest enzyme activity and gene expression values were observed for the OGG1 protein recognizing the modified 8oxoG. Conclusion: With the long-term use of an unbalanced diet, the levels of all DNA repair genes are increased, especially (significantly) Apex, Alox, and Ptgs, which strongly supports the hypothesis that an unbalanced diet induces oxidative stress that deregulates DNA repair mechanisms and may contribute to genome instability and tissue damage.
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Affiliation(s)
- Robert Paslawski
- Veterinary Insitute, Nicolaus Copernicus University in Toruń, Gagarina 7, 87-100 Toruń, Poland;
- WROVASC—Regional Specialist Hospital in Wroclaw, Research and Development Centre, Kamieńskiego 73a, 51-124 Wroclaw, Poland; (P.D.); (A.J.); (L.K.); (M.Z.); (A.S.)
| | - Paweł Kowalczyk
- The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland
| | - Urszula Paslawska
- Veterinary Insitute, Nicolaus Copernicus University in Toruń, Gagarina 7, 87-100 Toruń, Poland;
- WROVASC—Regional Specialist Hospital in Wroclaw, Research and Development Centre, Kamieńskiego 73a, 51-124 Wroclaw, Poland; (P.D.); (A.J.); (L.K.); (M.Z.); (A.S.)
| | - Jerzy Wiśniewski
- Department of Medical Biochemistry, Faculty of Medicine, Wroclaw Medical University, Chałubińskiego 10, 50-368 Wroclaw, Poland;
| | - Piotr Dzięgiel
- WROVASC—Regional Specialist Hospital in Wroclaw, Research and Development Centre, Kamieńskiego 73a, 51-124 Wroclaw, Poland; (P.D.); (A.J.); (L.K.); (M.Z.); (A.S.)
- Department of Histology and Embryology, Wroclaw Medical University, Chałubińskiego 6a, 50-368 Wroclaw, Poland
| | - Adrian Janiszewski
- WROVASC—Regional Specialist Hospital in Wroclaw, Research and Development Centre, Kamieńskiego 73a, 51-124 Wroclaw, Poland; (P.D.); (A.J.); (L.K.); (M.Z.); (A.S.)
- Faculty of Veterinary Medicine, Life Science Institute, Poznań University of Life Sciences, Wojska Polskiego 28, 60-637 Poznań, Poland
| | - Liliana Kiczak
- WROVASC—Regional Specialist Hospital in Wroclaw, Research and Development Centre, Kamieńskiego 73a, 51-124 Wroclaw, Poland; (P.D.); (A.J.); (L.K.); (M.Z.); (A.S.)
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, 31 Norwida St., 50-375 Wroclaw, Poland
| | - Maciej Zacharski
- WROVASC—Regional Specialist Hospital in Wroclaw, Research and Development Centre, Kamieńskiego 73a, 51-124 Wroclaw, Poland; (P.D.); (A.J.); (L.K.); (M.Z.); (A.S.)
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, 31 Norwida St., 50-375 Wroclaw, Poland
| | - Barbara Gawdzik
- Institute of Chemistry, Jan Kochanowski University, Świętokrzyska 15 G, 25-406 Kielce, Poland;
| | - Karol Kramkowski
- Department of Physical Chemistry, Medical University of Bialystok, Kilińskiego 1, 15-089 Białystok, Poland;
| | - Andrzej Szuba
- WROVASC—Regional Specialist Hospital in Wroclaw, Research and Development Centre, Kamieńskiego 73a, 51-124 Wroclaw, Poland; (P.D.); (A.J.); (L.K.); (M.Z.); (A.S.)
- Division of Angiology, Wroclaw Medical University, Pasteur 1, 50-367 Wroclaw, Poland
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14
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Xu W, Lai S, Zhao J, Wei S, Fang X, Liu Y, Rong X, Guo J. The blockade of the TGF-β pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity. Pharmacol Res Perspect 2024; 12:e1160. [PMID: 38174807 PMCID: PMC10765454 DOI: 10.1002/prp2.1160] [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: 09/18/2023] [Accepted: 11/21/2023] [Indexed: 01/05/2024] Open
Abstract
TGF-β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2-SREBP-1c mice and ob/ob mice, were used. TGF-β pathway showed up-regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF-β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre-administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild-type levels in aP2-SREBP-1c mice. In contrast, TGF-β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF-β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF-β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.
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Affiliation(s)
- Wen‐Dong Xu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Shui‐Zheng Lai
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Jia Zhao
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Shi‐Jie Wei
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Xue‐Ying Fang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Yi‐Yi Liu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Xiang‐Lu Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
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15
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Kajita K, Ishii I, Mori I, Asano M, Fuwa M, Morita H. Sphingosine 1-Phosphate Regulates Obesity and Glucose Homeostasis. Int J Mol Sci 2024; 25:932. [PMID: 38256005 PMCID: PMC10816022 DOI: 10.3390/ijms25020932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 01/04/2024] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
One of the major global health and welfare issues is the treatment of obesity and associated metabolic disorders, such as type 2 diabetes mellitus and nonalcoholic fatty liver disease. Obesity, caused by the excessive accumulation of triglycerides in adipose tissues, induces adipocyte dysfunction, followed by inflammation, in adipose tissues and lipotoxicity in nonadipose tissues. Several studies have shown that obesity and glucose homeostasis are influenced by sphingolipid mediators, including ceramide and sphingosine 1-phosphate (S1P). Cellular accumulation of ceramide impairs pancreatic β-cell survival, confers insulin resistance in the liver and the skeletal muscle, and deteriorates adipose tissue inflammation via unknown molecular mechanisms. The roles of S1P are more complicated, because there are five cell-surface S1P receptors (S1PRs: S1P1-5) which have altered functions, different cellular expression patterns, and inapparent intracellular targets. Recent findings, including those by our group, support the notable concept that the pharmacological activation of S1P1 or S1P3 improves obesity and associated metabolic disorders, whereas that of S1P2 has the opposite effect. In addition, the regulation of S1P production by sphingosine kinase (SphK) is an essential factor affecting glucose homeostasis. This review summarizes the current knowledge on SphK/S1P/S1PR signaling in and against obesity, insulin resistance, and associated disorders.
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Affiliation(s)
- Kazuo Kajita
- Department of Health and Nutrition, Faculty of Home Economics, Gifu Women’s University, 80 Taromaru, Gifu 501-2592, Japan
| | - Isao Ishii
- Department of Health Chemistry, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida 194-8543, Japan
| | - Ichiro Mori
- Department of General Medicine and General Internal Medicine, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (I.M.); (M.A.); (M.F.); (H.M.)
| | - Motochika Asano
- Department of General Medicine and General Internal Medicine, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (I.M.); (M.A.); (M.F.); (H.M.)
| | - Masayuki Fuwa
- Department of General Medicine and General Internal Medicine, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (I.M.); (M.A.); (M.F.); (H.M.)
| | - Hiroyuki Morita
- Department of General Medicine and General Internal Medicine, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (I.M.); (M.A.); (M.F.); (H.M.)
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16
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Contreras PH, Vigil P. Across-species benefits of adrenalectomy on congenital generalized lipoatrophic diabetes: a review. Front Endocrinol (Lausanne) 2024; 14:1151873. [PMID: 38260129 PMCID: PMC10801166 DOI: 10.3389/fendo.2023.1151873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 11/22/2023] [Indexed: 01/24/2024] Open
Abstract
Two adrenalectomies py -45erformed fourteen years apart notoriously alleviated insulin resistance in a female teenager with Congenital Generalized Lipoatrophy (CGL, 1988) and in a murine model of CGL (2002). Following a successful therapeutic trial with anti-glucocorticoids, we performed the first surgical procedure on an 18-year-old girl. Before surgery, the anti-glucocorticoid therapy produced a rapid and striking drop in fasting serum insulin levels (from over 400 to 7.0 mU/L) and a slower -but impressive- fall in fasting serum triglycerides from 7,400 to 220-230 mg/dL. In contrast, fasting serum glucose levels dropped more slowly, from 225-290 to 121-138 mg/dL. Two weeks following total adrenalectomy, the fasting serum glucose level was 98 mg/dL, with a corresponding serum insulin level of 10 mU/L. During an Oral Glucose Tolerance Test, the 2-hour serum glucose was 210 mg/dL, and serum insulin values during the test did not exceed 53 mU/L. In 2002, the A-ZIP/F1 hypoleptinemic mouse had its adrenal glands removed. Even though this CGL model does not respond well to leptin replacement, an infusion of recombinant leptin reduced the characteristic hypercorticosteronemia of this murine model of CGL. Adrenalectomy in this transgenic mouse improved insulin sensitivity in the liver and muscle. In summary, adrenalectomy -in both a human and a mouse case of CGL- limited adipose tissue exposure to corticosteroid action and led to a notorious metabolic improvement. On a broader scenario, given that leptin restrains the adrenal axis, the reduced leptin activity of the leptin resistance displayed by obese subjects should lead to adrenal axis overactivity. This overactivity should result in elevated serum levels of free cortisol, free fatty acids, and glycerol. In this manner, leptin resistance should lead to peripheral (adipose tissue, liver, and muscle) insulin resistance and islet beta-cell apoptosis, paving the way to Type 2 diabetes.
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Affiliation(s)
- Patricio H. Contreras
- Reproductive Endocrinology Unit, Reproductive Health Research Institute, Santiago, Chile
- Endocrine and Gynecology Units, Fundación Médica San Cristóbal, Santiago, Chile
| | - Pilar Vigil
- Reproductive Endocrinology Unit, Reproductive Health Research Institute, Santiago, Chile
- Endocrine and Gynecology Units, Fundación Médica San Cristóbal, Santiago, Chile
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17
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Tiwari M, Mcilroy GD. From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy. Diabet Med 2023; 40:e15214. [PMID: 37638531 DOI: 10.1111/dme.15214] [Citation(s) in RCA: 2] [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] [Received: 06/26/2023] [Revised: 08/19/2023] [Accepted: 08/22/2023] [Indexed: 08/29/2023]
Abstract
AIMS Lipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life-threatening, with limited treatment options and a lack of specialised expertise. This review aims to raise awareness of lipodystrophy disorders and highlights therapeutic strategies to restore adipose tissue functionality. METHODS Extensive research has been conducted, including both historical and recent advances. We have examined and summarised the literature to provide an overview of potential strategies to restore adipose tissue functionality and treat/reverse metabolic complications in lipodystrophy disorders. RESULTS A wealth of basic and clinical research has investigated various therapeutic approaches for lipodystrophy. These include ground-breaking methods such as adipose tissue transplantation, innovative leptin replacement therapy, targeted inhibition of lipolysis and cutting-edge gene and cell therapies. Each approach shows great potential in addressing the complex challenges posed by lipodystrophy. CONCLUSIONS Lipodystrophy disorders require urgent attention and innovative treatments. Through rigorous basic and clinical research, several promising therapeutic strategies have emerged that could restore adipose tissue functionality and reverse the severe metabolic complications associated with this condition. However, further research and collaboration between academics, clinicians, patient advocacy groups and pharmaceutical companies will be crucial in transforming these scientific breakthroughs into effective and viable treatment options for individuals and families affected by lipodystrophy. Fostering such interdisciplinary partnerships could pave the way for a brighter future for those battling this debilitating disorder.
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Affiliation(s)
- Mansi Tiwari
- The Rowett Institute, University of Aberdeen, Aberdeen, UK
- Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK
| | - George D Mcilroy
- The Rowett Institute, University of Aberdeen, Aberdeen, UK
- Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK
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18
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Altarejos JY, Pangilinan J, Podgrabinska S, Akinci B, Foss-Freitas M, Neidert AH, Ray Y, Zheng W, Kim S, Kamat V, Huang M, Min S, Mastaitis J, Dominguez-Gutierrez G, Kim JH, Stevis P, Huang T, Zambrowicz B, Olson WC, Godin S, Bradley E, Gewitz AD, Baker M, Hench R, Davenport MS, Chenevert TL, DiPaola F, Yancopoulos GD, Murphy AJ, Herman GA, Musser BJ, Dansky H, Harp J, Gromada J, Sleeman MW, Oral EA, Olenchock BA. Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency. Sci Transl Med 2023; 15:eadd4897. [PMID: 37992152 DOI: 10.1126/scitranslmed.add4897] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 10/25/2023] [Indexed: 11/24/2023]
Abstract
Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.
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Affiliation(s)
- Judith Y Altarejos
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Jeffrey Pangilinan
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Simona Podgrabinska
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Baris Akinci
- Izmir Biomedicine and Genome Center, 35340 Izmir, Turkey
| | - Maria Foss-Freitas
- Brehm Center for Diabetes Research, Caswell Diabetes Institute, and Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA
| | - Adam H Neidert
- Brehm Center for Diabetes Research, Caswell Diabetes Institute, and Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yonaton Ray
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Wenjun Zheng
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Steven Kim
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Vishal Kamat
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Meilin Huang
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Soo Min
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Jason Mastaitis
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | | | - Jee-Hae Kim
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Panayiotis Stevis
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Tammy Huang
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Brian Zambrowicz
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - William C Olson
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Stephen Godin
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Elizabeth Bradley
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Andrew D Gewitz
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Mark Baker
- Brehm Center for Diabetes Research, Caswell Diabetes Institute, and Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rita Hench
- Brehm Center for Diabetes Research, Caswell Diabetes Institute, and Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA
| | - Matthew S Davenport
- Department of Radiology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Thomas L Chenevert
- Department of Radiology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Frank DiPaola
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - George D Yancopoulos
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Andrew J Murphy
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Gary A Herman
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Bret J Musser
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Hayes Dansky
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Joyce Harp
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Jesper Gromada
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Mark W Sleeman
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Elif A Oral
- Brehm Center for Diabetes Research, Caswell Diabetes Institute, and Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA
| | - Benjamin A Olenchock
- Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
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19
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Shin J, Toyoda S, Okuno Y, Hayashi R, Nishitani S, Onodera T, Sakamoto H, Ito S, Kobayashi S, Nagao H, Kita S, Otsuki M, Fukuhara A, Nagata K, Shimomura I. HSP47 levels determine the degree of body adiposity. Nat Commun 2023; 14:7319. [PMID: 37951979 PMCID: PMC10640548 DOI: 10.1038/s41467-023-43080-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 10/31/2023] [Indexed: 11/14/2023] Open
Abstract
Adiposity varies among individuals with the influence of diverse physiological, pathological, environmental, hormonal, and genetic factors, but a unified molecular basis remains elusive. Here, we identify HSP47, a collagen-specific chaperone, as a key determinant of body adiposity. HSP47 expression is abundant in adipose tissue; increased with feeding, overeating, and obesity; decreased with fasting, exercise, calorie restriction, bariatric surgery, and cachexia; and correlated with fat mass, BMI, waist, and hip circumferences. Insulin and glucocorticoids, respectively, up- and down-regulate HSP47 expression. In humans, the increase of HSP47 gene expression by its intron or synonymous variants is associated with higher body adiposity traits. In mice, the adipose-specific knockout or pharmacological inhibition of HSP47 leads to lower body adiposity compared to the control. Mechanistically, HSP47 promotes collagen dynamics in the folding, secretion, and interaction with integrin, which activates FAK signaling and preserves PPARγ protein from proteasomal degradation, partly related to MDM2. The study highlights the significance of HSP47 in determining the amount of body fat individually and under various circumstances.
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Affiliation(s)
- Jihoon Shin
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
- Department of Diabetes Care Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
| | - Shinichiro Toyoda
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yosuke Okuno
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Reiko Hayashi
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shigeki Nishitani
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Toshiharu Onodera
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, USA
| | - Haruyo Sakamoto
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shinya Ito
- Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan
| | - Sachiko Kobayashi
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hirofumi Nagao
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shunbun Kita
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Adipose Management, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Michio Otsuki
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Endocrinology, Graduate School of Medical Science, Tokyo Women's Medical University, Tokyo, Japan
| | - Atsunori Fukuhara
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Adipose Management, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Kazuhiro Nagata
- Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto, Japan
- JT Biohistory Research Hall, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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20
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Chitraju C, Fischer AW, Ambaw YA, Wang K, Yuan B, Hui S, Walther TC, Farese RV. Mice lacking triglyceride synthesis enzymes in adipose tissue are resistant to diet-induced obesity. eLife 2023; 12:RP88049. [PMID: 37782317 PMCID: PMC10545428 DOI: 10.7554/elife.88049] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023] Open
Abstract
Triglycerides (TGs) in adipocytes provide the major stores of metabolic energy in the body. Optimal amounts of TG stores are desirable as insufficient capacity to store TG, as in lipodystrophy, or exceeding the capacity for storage, as in obesity, results in metabolic disease. We hypothesized that mice lacking TG storage in adipocytes would result in excess TG storage in cell types other than adipocytes and severe lipotoxicity accompanied by metabolic disease. To test this hypothesis, we selectively deleted both TG synthesis enzymes, DGAT1 and DGAT2, in adipocytes (ADGAT DKO mice). As expected with depleted energy stores, ADGAT DKO mice did not tolerate fasting well and, with prolonged fasting, entered torpor. However, ADGAT DKO mice were unexpectedly otherwise metabolically healthy and did not accumulate TGs ectopically or develop associated metabolic perturbations, even when fed a high-fat diet. The favorable metabolic phenotype resulted from activation of energy expenditure, in part via BAT (brown adipose tissue) activation and beiging of white adipose tissue. Thus, the ADGAT DKO mice provide a fascinating new model to study the coupling of metabolic energy storage to energy expenditure.
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Affiliation(s)
- Chandramohan Chitraju
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public HealthBostonUnited States
- Department of Cell Biology, Harvard Medical SchoolBostonUnited States
| | - Alexander W Fischer
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public HealthBostonUnited States
- Department of Cell Biology, Harvard Medical SchoolBostonUnited States
| | - Yohannes A Ambaw
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public HealthBostonUnited States
- Department of Cell Biology, Harvard Medical SchoolBostonUnited States
- Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Kun Wang
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public HealthBostonUnited States
- Department of Cell Biology, Harvard Medical SchoolBostonUnited States
| | - Bo Yuan
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public HealthBostonUnited States
| | - Sheng Hui
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public HealthBostonUnited States
| | - Tobias C Walther
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public HealthBostonUnited States
- Department of Cell Biology, Harvard Medical SchoolBostonUnited States
- Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
- Broad Institute of Harvard and MITCambridgeUnited States
- Howard Hughes Medical InstituteBostonUnited States
| | - Robert V Farese
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public HealthBostonUnited States
- Department of Cell Biology, Harvard Medical SchoolBostonUnited States
- Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
- Broad Institute of Harvard and MITCambridgeUnited States
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21
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Umano GR, Cirillo G, Sanchez G, Rondinelli G, Foderini MV, Ferrara S, Di Sessa A, Marzuillo P, Papparella A, Santoro N, Miraglia Del Giudice E. The lncOb rs10487505 polymorphism impairs insulin sensitivity and glucose tolerance in children and adolescents with obesity. Obesity (Silver Spring) 2023; 31:2359-2364. [PMID: 37550829 DOI: 10.1002/oby.23835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/17/2023] [Accepted: 05/11/2023] [Indexed: 08/09/2023]
Abstract
OBJECTIVE Leptin plays a key role in the regulation of body weight and other endocrine systems. Recently, impairment of leptin gene transcription due to genetic variations in a long noncoding RNA (lncOb) has been described. This retrospective study aims to characterize the clinical and metabolic phenotype of children and adolescents with obesity who were homozygous for the lncOb rs10487505 leptin lowering allele. METHODS Enrolled children underwent an anthropometrical evaluation, biochemical assessment, and genotyping for lncOb rs10487505. Plasma leptin levels were assessed in 150 participants. A total of 434 patients were included and divided into two groups according to rs10487505 recessive inheritance (CC vs. GG/GC). RESULTS Children who were homozygous for the C allele showed higher fasting insulin (p = 0.01), homeostasis model assessment of insulin resistance (p = 0.01), lower whole-body insulin sensitivity index (p = 0.02), and lower disposition index (p = 0.03). Moreover, CC patients presented with a higher prevalence of prediabetes (9.3% vs. 3.4%, p = 0.04) and a 2.9-fold (95% CI: 1.1-7.9, p = 0.04) higher risk of prediabetes compared with G-carriers independently from confounders. Leptin plasma levels were significantly lower in the CC group (p = 0.002). Hormone levels correlated with BMI z score (r = 0.19, p = 0.04), fasting insulin (r = -0.34, p < 0.0001), homeostasis model assessment of insulin resistance (r = -0.33, p < 0.0001), and disposition index (r = 0.20, p = 0.04). CONCLUSIONS The lncOb rs10487505 polymorphism affects leptin circulating levels, worsens insulin resistance, and heightens the risk of prediabetes in children and adolescents with obesity.
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Affiliation(s)
- Giuseppina Rosaria Umano
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Grazia Cirillo
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Gianmaria Sanchez
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Giulia Rondinelli
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Maria Vittoria Foderini
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Serena Ferrara
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Anna Di Sessa
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Pierluigi Marzuillo
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Alfonso Papparella
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Nicola Santoro
- Department of Medicine and Health Sciences, "V. Tiberio" University of Molise, Campobasso, Italy
- Department of Pediatrics, Kansas University Medical Center, Kansas City, Kansas, USA
- Department of Pediatrics, School of Medicine, Yale University, New Haven, Connecticut, USA
| | - Emanuele Miraglia Del Giudice
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
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22
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Lim JY, Kim E. The Role of Organokines in Obesity and Type 2 Diabetes and Their Functions as Molecular Transducers of Nutrition and Exercise. Metabolites 2023; 13:979. [PMID: 37755259 PMCID: PMC10537761 DOI: 10.3390/metabo13090979] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 09/28/2023] Open
Abstract
Maintaining systemic homeostasis requires the coordination of different organs and tissues in the body. Our bodies rely on complex inter-organ communications to adapt to perturbations or changes in metabolic homeostasis. Consequently, the liver, muscle, and adipose tissues produce and secrete specific organokines such as hepatokines, myokines, and adipokines in response to nutritional and environmental stimuli. Emerging evidence suggests that dysregulation of the interplay of organokines between organs is associated with the pathophysiology of obesity and type 2 diabetes (T2D). Strategies aimed at remodeling organokines may be effective therapeutic interventions. Diet modification and exercise have been established as the first-line therapeutic intervention to prevent or treat metabolic diseases. This review summarizes the current knowledge on organokines secreted by the liver, muscle, and adipose tissues in obesity and T2D. Additionally, we highlighted the effects of diet/nutrition and exercise on the remodeling of organokines in obesity and T2D. Specifically, we investigated the ameliorative effects of caloric restriction, selective nutrients including ω3 PUFAs, selenium, vitamins, and metabolites of vitamins, and acute/chronic exercise on the dysregulation of organokines in obesity and T2D. Finally, this study dissected the underlying molecular mechanisms by which nutrition and exercise regulate the expression and secretion of organokines in specific tissues.
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Affiliation(s)
- Ji Ye Lim
- Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin St., Houston, TX 77030, USA
| | - Eunju Kim
- Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin St., Houston, TX 77030, USA
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23
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Rahman SMK, Sasaki S, Uyama T, Hussain Z, Sikder MM, Saiga H, Ohmura-Hoshino M, Ohta KI, Miki Y, Hoshino K, Ueno M, Murakami M, Ueda N. PLAAT1 deficiency alleviates high-fat diet-induced hepatic lipid accumulation in mice. FASEB J 2023; 37:e23032. [PMID: 37330992 DOI: 10.1096/fj.202201033r] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 05/23/2023] [Accepted: 06/02/2023] [Indexed: 06/20/2023]
Abstract
The phospholipase A and acyltransferase (PLAAT) family is composed of three isoforms in mice (PLAAT1, 3, and 5), all of which function as phospholipid-metabolizing enzymes exhibiting phospholipase A1 /A2 and acyltransferase activities. Plaat3-deficient (Plaat3-/- ) mice were previously reported to show lean phenotype and remarkable hepatic fat accumulation under high-fat diet (HFD) feeding, while Plaat1-/- mice have not been analyzed. In the present study, we generated Plaat1-/- mice and investigated the effects of PLAAT1 deficiency on HFD-induced obesity, hepatic lipid accumulation, and insulin resistance. After HFD treatment, PLAAT1 deficiency caused a lower body weight gain compared to wild-type mice. Plaat1-/- mice also showed reduced liver weight with negligible hepatic lipid accumulation. In accordance with these findings, PLAAT1 deficiency improved HFD-induced hepatic dysfunction and lipid metabolism disorders. Lipidomics analysis in the liver revealed that in Plaat1-/- mice, the levels of various glycerophospholipids tended to increase, while all classes of lysophospholipids examined tended to decrease, suggesting that PLAAT1 functions as phospholipase A1 /A2 in the liver. Interestingly, the HFD treatment of wild-type mice significantly increased the mRNA level of PLAAT1 in the liver. Furthermore, the deficiency did not appear to elevate the risk of insulin resistance in contrast to PLAAT3 deficiency. These results suggested that the suppression of PLAAT1 improves HFD-induced overweight and concomitant hepatic lipid accumulation.
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Affiliation(s)
- S M Khaledur Rahman
- Department of Biochemistry, Kagawa University School of Medicine, Kagawa, Japan
| | - Sumire Sasaki
- Department of Biochemistry, Kagawa University School of Medicine, Kagawa, Japan
| | - Toru Uyama
- Department of Biochemistry, Kagawa University School of Medicine, Kagawa, Japan
| | - Zahir Hussain
- Department of Biochemistry, Kagawa University School of Medicine, Kagawa, Japan
- Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | | | - Hiroyuki Saiga
- Department of Immunology, Kagawa University School of Medicine, Kagawa, Japan
| | - Mari Ohmura-Hoshino
- Department of Immunology, Kagawa University School of Medicine, Kagawa, Japan
- Department of Medical Technology, School of Nursing and Medical Care, Yokkaichi Nursing and Medical Care University, Mie, Japan
| | - Ken-Ichi Ohta
- Department of Anatomy and Neurobiology, Kagawa University School of Medicine, Kagawa, Japan
| | - Yoshimi Miki
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Katsuaki Hoshino
- Department of Immunology, Kagawa University School of Medicine, Kagawa, Japan
| | - Masaki Ueno
- Department of Inflammation Pathology, Kagawa University School of Medicine, Kagawa, Japan
| | - Makoto Murakami
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Natsuo Ueda
- Department of Biochemistry, Kagawa University School of Medicine, Kagawa, Japan
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24
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Weninger SN, Ding A, Browne EN, Frost ML, Schiro G, Laubitz D, Duca FA. Longitudinal Characterization of the Gut Microbiota in the Diabetic ZDSD Rat Model and Therapeutic Potential of Oligofructose. Metabolites 2023; 13:660. [PMID: 37233701 PMCID: PMC10220957 DOI: 10.3390/metabo13050660] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/03/2023] [Accepted: 05/11/2023] [Indexed: 05/27/2023] Open
Abstract
The complex development of type 2 diabetes (T2D) creates challenges for studying the progression and treatment of the disease in animal models. A newly developed rat model of diabetes, the Zucker Diabetic Sprague Dawley (ZDSD) rat, closely parallels the progression of T2D in humans. Here, we examine the progression of T2D and associated changes in the gut microbiota in male ZDSD rats and test whether the model can be used to examine the efficacy of potential therapeutics such as prebiotics, specifically oligofructose, that target the gut microbiota. Bodyweight, adiposity, and fed/fasting blood glucose and insulin were recorded over the course of the study. Glucose and insulin tolerance tests were performed, and feces collected at 8, 16, and 24 weeks of age for short-chain fatty acids and microbiota analysis using 16s rRNA gene sequencing. At the end of 24 weeks of age, half of the rats were supplemented with 10% oligofructose and tests were repeated. We observed a transition from healthy/nondiabetic to prediabetic and overtly diabetic states, via worsened insulin and glucose tolerance and significant increases in fed/fasted glucose, followed by a significant decrease in circulating insulin. Acetate and propionate levels were significantly increased in the overt diabetic state compared to healthy and prediabetic. Microbiota analysis demonstrated alterations in the gut microbiota with shifts in alpha and beta diversity as well as alterations in specific bacterial genera in healthy compared to prediabetic and diabetic states. Oligofructose treatment improved glucose tolerance and shifted the cecal microbiota of the ZDSD rats during late-stage diabetes. These findings underscore the translational potential of ZDSD rats as a model of T2D and highlight potential gut bacteria that could impact the development of the disease or serve as a biomarker for T2D. Additionally, oligofructose treatment was able to moderately improve glucose homeostasis.
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Affiliation(s)
- Savanna N. Weninger
- Department of Physiological Sciences, University of Arizona, Tucson, AZ 85721, USA
| | - Angela Ding
- Department of Physiological Sciences, University of Arizona, Tucson, AZ 85721, USA
| | - Elizabeth N. Browne
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA
| | - Morgan L. Frost
- School of Animal and Comparative Biomedical Sciences, College of Agricultural and Life Sciences, University of Arizona, Tucson, AZ 85721, USA
| | - Gabriele Schiro
- The PANDA Core for Genomics and Microbiome Research, Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA
| | - Daniel Laubitz
- The PANDA Core for Genomics and Microbiome Research, Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA
| | - Frank A. Duca
- School of Animal and Comparative Biomedical Sciences, College of Agricultural and Life Sciences, University of Arizona, Tucson, AZ 85721, USA
- BIO5 Institute, University of Arizona, Tucson, AZ 85721, USA
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25
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Mathur M, Yeh YT, Arya RK, Jiang L, Pornour M, Chen W, Ma Y, Gao B, He L, Ying Z, Xue B, Shi H, Choi Y, Yu L. Adipose lipolysis is important for ethanol to induce fatty liver in the National Institute on Alcohol Abuse and Alcoholism murine model of chronic and binge ethanol feeding. Hepatology 2023; 77:1688-1701. [PMID: 35844150 PMCID: PMC9845426 DOI: 10.1002/hep.32675] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 01/21/2023]
Abstract
BACKGROUND AND AIMS Alcohol-associated liver disease (ALD) pathologies include steatosis, inflammation, and injury, which may progress to fibrosis, cirrhosis, and cancer. The liver receives ~60% of fatty acids from adipose tissue triglyceride hydrolysis, but the role of this lipolytic pathway in ALD development has not been directly examined in any genetic animal models with selective inactivation of adipose lipolysis. APPROACH AND RESULTS Using adipose-specific comparative gene identification-58 (CGI-58) knockout (FAT-KO) mice, a model of impaired adipose lipolysis, we show that mice deficient in adipose lipolysis are almost completely protected against ethanol-induced hepatic steatosis and lipid peroxidation when subjected to the National Institute on Alcohol Abuse and Alcoholism chronic and binge ethanol feeding model. This is unlikely due to reduced lipid synthesis because this regimen of ethanol feeding down-regulated hepatic expression of lipogenic genes similarly in both genotypes. In the pair-fed group, FAT-KO relative to control mice displayed increased hepatocyte injury, neutrophil infiltration, and activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the liver; and none of these were exacerbated by ethanol feeding. Activation of STAT3 is associated with a marked increase in hepatic leptin receptor mRNA expression and adipose inflammatory cell infiltration. CONCLUSIONS Our findings establish a critical role of adipose lipolysis in driving hepatic steatosis and oxidative stress during ALD development.
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Affiliation(s)
- Mallika Mathur
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Yu-Te Yeh
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Rakesh K. Arya
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Long Jiang
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Majid Pornour
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Weiping Chen
- Genomics Core, National Institute of Diabetes & Digestive & Kidney Disease, NIH, Bethesda, MD 20892, USA
| | - Yinyan Ma
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute of Alcohol Abuse and Alcoholism, NIH, Bethesda, MD20892, USA
| | - Ling He
- Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Zhekang Ying
- Department of Medicine Cardiology Division, University of Maryland School of Medicine, Baltimore, MD 21021, USA
| | - Bingzhong Xue
- Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA 30303, USA
| | - Hang Shi
- Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA 30303, USA
| | - Youngshim Choi
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Liqing Yu
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Robledo F, González-Hodar L, Tapia P, Figueroa AM, Ezquer F, Cortés V. Spheroids derived from the stromal vascular fraction of adipose tissue self-organize in complex adipose organoids and secrete leptin. Stem Cell Res Ther 2023; 14:70. [PMID: 37024989 PMCID: PMC10080976 DOI: 10.1186/s13287-023-03262-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 03/06/2023] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND Adipose tissue-derived stromal vascular fraction (SVF) harbors multipotent cells with potential therapeutic relevance. We developed a method to form adipose spheroids (AS) from the SVF with complex organoid structure and enhanced leptin secretion upon insulin stimulation. METHODS SVF was generated from the interscapular brown adipose tissue of newborn mice. Immunophenotype and stemness of cultured SVF were determined by flow cytometry and in vitro differentiation, respectively. Spheroids were generated in hanging drops and non-adherent plates and compared by morphometric methods. The adipogenic potential was compared between preadipocyte monolayers and spheroids. Extracellular leptin was quantified by immunoassay. Lipolysis was stimulated with isoprenaline and quantified by colorimetric methods. AS viability and ultrastructure were determined by confocal and transmission electron microscopy analyses. RESULTS Cultured SVF contained Sca1 + CD29 + CD44 + CD11b- CD45- CD90- cells with adipogenic and chondrogenic but no osteogenic potential. Culture on non-adherent plates yielded the highest quantity and biggest size of spheroids. Differentiation of AS for 15 days in a culture medium supplemented with insulin and rosiglitazone resulted in greater Pparg, Plin1, and Lep expression compared to differentiated adipocytes monolayers. AS were viable and maintained leptin secretion even in the absence of adipogenic stimulation. Glycerol release after isoprenaline stimulation was higher in AS compared to adipocytes in monolayers. AS were composed of outer layers of unilocular mature adipocytes and an inner structure composed of preadipocytes, immature adipocytes and an abundant loose extracellular matrix. CONCLUSION Newborn mice adipose SVF can be efficiently differentiated into leptin-secreting AS. Prolonged stimulation with insulin and rosiglitazone allows the formation of structurally complex adipose organoids able to respond to adrenergic lipolytic stimulation.
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Affiliation(s)
- Fermín Robledo
- Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Lila González-Hodar
- Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo Tapia
- Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ana-María Figueroa
- Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Fernando Ezquer
- Center for Regenerative Medicine, School of Medicine, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - Víctor Cortés
- Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Calcaterra V, Magenes VC, Rossi V, Fabiano V, Mameli C, Zuccotti G. Lipodystrophies in non-insulin-dependent children: Treatment options and results from recombinant human leptin therapy. Pharmacol Res 2023; 187:106629. [PMID: 36566927 DOI: 10.1016/j.phrs.2022.106629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/10/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
Lipodystrophy is a general definition containing different pathologies which, except for those observed in insulin-treated subjects falling outside the scope of this paper, are characterized by total or partial lack of body fat, that, according to the amount of missing adipose tissue, are divided in generalized or partial lipodystrophy. These diseases are characterized by leptin deficiency, which often leads to metabolic derangement, causing insulin resistance, dyslipidemia, and increasing cardiovascular risk. In this narrative review, we presentend the clinical presentation of different types of lipodystrophies and metabolic unbalances related to disease in children and adolescents, focusing on the main treatment options and the novel results from recombinant human leptin (metreleptin) therapy. Milestones in the management of lipodystrophy include lifestyle modification as diet and physical activity, paired with hypoglycemic drugs, insulin, hypolipidemic drugs, and other drugs with the aim of treating lipodystrophy complications. Metreleptin has been recently approved for pediatric patients with general lipodystrophy (GL)> 2 years of age and for children with partial lipodystrophy (PL)> 12 years of age not controlled with conventional therapies. New therapeutic strategies are currently being investigated, especially for patients with PL forms, specifically, liver-targeted therapies. Further studies are needed to achieve the most specific and precise treatment possible.
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Affiliation(s)
- Valeria Calcaterra
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy.
| | | | - Virginia Rossi
- Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy
| | - Valentina Fabiano
- Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy; Department of Biomedical and Clinical Sciences, Università di Milano, 20122 Milan, Italy
| | - Chiara Mameli
- Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy; Department of Biomedical and Clinical Sciences, Università di Milano, 20122 Milan, Italy
| | - Gianvincenzo Zuccotti
- Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy; Department of Biomedical and Clinical Sciences, Università di Milano, 20122 Milan, Italy
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Leptin treatment has vasculo-protective effects in lipodystrophic mice. Proc Natl Acad Sci U S A 2022; 119:e2110374119. [PMID: 36161905 PMCID: PMC9546548 DOI: 10.1073/pnas.2110374119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Lipodystrophy syndromes are characterized by loss of adipose tissue, metabolic complications, and accelerated atherosclerosis. Adipose tissue deficiency results in reduced levels of the adipokine leptin. We investigated the effects of leptin on the functional properties of endothelial cells and atherogenesis in lipodystrophy. Leptin reduced endothelial to mesenchymal transition-induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Leptin administration in a lipodystrophy and atherosclerosis mouse model reduced plaque protrusion and endothelial cells with mesenchymal gene expression in vascular plaques. The effects were mediated by the growth/differentiation factor 15. The data identify an important role for leptin in controlling endothelial cell function in lipodystrophy syndromes. Lipodystrophy syndromes (LDs) are characterized by loss of adipose tissue, metabolic complications such as dyslipidemia, insulin resistance, and fatty liver disease, as well as accelerated atherosclerosis. As a result of adipose tissue deficiency, the systemic concentration of the adipokine leptin is reduced. A current promising therapeutic option for patients with LD is treatment with recombinant leptin (metreleptin), resulting in reduced risk of mortality. Here, we investigate the effects of leptin on endothelial to mesenchymal transition (EndMT), which impair the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation and TGF-β2–induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Treatment of lipodystrophic- and atherosclerosis-prone animals (Ldlr−/−; aP2-nSrebp1c-Tg) with leptin reduced macrophage accumulation in atherosclerotic lesions, vascular plaque protrusion, and the number of endothelial cells with mesenchymal gene expression, confirming a reduction in EndMT in LD after leptin treatment. Treatment with leptin inhibited LD-mediated induction of the proatherosclerotic cytokine growth/differentiation factor 15 (GDF15). Inhibition of GDF15 reduced EndMT induction triggered by plasma from patients with LD. Our study reveals that in addition to the effects on adipose tissue function, leptin treatment exerts beneficial effects protecting endothelial function and identity in LD by reducing GDF15.
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Abstract
Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are essential to normal growth, metabolism, and body composition, but in acromegaly, excesses of these hormones strikingly alter them. In recent years, the use of modern methodologies to assess body composition in patients with acromegaly has revealed novel aspects of the acromegaly phenotype. In particular, acromegaly presents a unique pattern of body composition changes in the setting of insulin resistance that we propose herein to be considered an acromegaly-specific lipodystrophy. The lipodystrophy, initiated by a distinctive GH-driven adipose tissue dysregulation, features insulin resistance in the setting of reduced visceral adipose tissue (VAT) mass and intra-hepatic lipid (IHL) but with lipid redistribution, resulting in ectopic lipid deposition in muscle. With recovery of the lipodystrophy, adipose tissue mass, especially that of VAT and IHL, rises, but insulin resistance is lessened. Abnormalities of adipose tissue adipokines may play a role in the disordered adipose tissue metabolism and insulin resistance of the lipodystrophy. The orexigenic hormone ghrelin and peptide Agouti-related peptide may also be affected by active acromegaly as well as variably by acromegaly therapies, which may contribute to the lipodystrophy. Understanding the pathophysiology of the lipodystrophy and how acromegaly therapies differentially reverse its features may be important to optimizing the long-term outcome for patients with this disease. This perspective describes evidence in support of this acromegaly lipodystrophy model and its relevance to acromegaly pathophysiology and the treatment of patients with acromegaly.
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Affiliation(s)
- Pamela U. Freda
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
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30
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Insulin sensitivity is associated with the observed variation of de novo lipid synthesis and body composition in finishing pigs. Sci Rep 2022; 12:14586. [PMID: 36028540 PMCID: PMC9418310 DOI: 10.1038/s41598-022-18799-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 08/19/2022] [Indexed: 11/08/2022] Open
Abstract
Variations in body composition among pigs can be associated with insulin sensitivity given the insulin anabolic effect. The study objectives were to characterize this association and to compare de novo lipogenesis and the gene expression in the adipose tissue of pigs of the same genetic background. Thirty 30-95 kg of body weight (BW) pigs, catheterized in the jugular vein participated into an oral glucose tolerance test (OGTT; 1.75 g glucose/kg of BW) to calculate insulin-related indexes. The 8 fattest and the 8 leanest pigs were used to determine the relative mRNA abundance of studied genes. The rate of lipogenesis was assessed by incorporation of [U-13C]glucose into lipids. The QUICKI and Matsuda indexes negatively correlated with total body lipids (r = - 0.67 and r = - 0.59; P < 0.01) and de novo lipogenesis (r = - 0.58; P < 0.01). Fat pigs had a higher expression level of lipogenic enzymes (ACACA, ACLY; P < 0.05) than lean pigs. The reduced insulin sensitivity in fat pigs was associated with a higher expression level of glucose-6-phosphate dehydrogenase (G6PD) and a lower expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ). In conclusion, pigs with increased body lipids have lower insulin sensitivity which is associated with increased de novo lipogenesis.
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Jang JH, Lee JW, Cho MJ, Hwang B, Kwon MG, Kim DH, Lee NK, Lee J, Park YJ, Yang YR, Kim J, Kim YH, An TH, Oh KJ, Bae KH, Park JG, Min JK. KLHL3 deficiency in mice ameliorates obesity, insulin resistance, and nonalcoholic fatty liver disease by regulating energy expenditure. EXPERIMENTAL & MOLECULAR MEDICINE 2022; 54:1250-1261. [PMID: 36028759 PMCID: PMC9440235 DOI: 10.1038/s12276-022-00833-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 05/17/2022] [Accepted: 06/23/2022] [Indexed: 11/13/2022]
Abstract
Obesity is a growing global epidemic that can cause serious adverse health consequences, including insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). Obesity development can be attributed to energy imbalance and metabolic inflexibility. Here, we demonstrated that lack of Kelch-like protein 3 (KLHL3) mitigated the development of obesity, IR, and NAFLD by increasing energy expenditure. KLHL3 mutations in humans cause Gordon’s hypertension syndrome; however, the role of KLHL3 in obesity was previously unknown. We examined differences in obesity-related parameters between control and Klhl3−/− mice. A significant decrease in body weight concomitant with fat mass loss and improved IR and NAFLD were observed in Klhl3−/− mice fed a high-fat (HF) diet and aged. KLHL3 deficiency inhibited obesity, IR, and NAFLD by increasing energy expenditure with augmentation of O2 consumption and CO2 production. Delivering dominant-negative (DN) Klhl3 using adeno-associated virus into mice, thereby dominantly expressing DN-KLHL3 in the liver, ameliorated diet-induced obesity, IR, and NAFLD. Finally, adenoviral overexpression of DN-KLHL3, but not wild-type KLHL3, in hepatocytes revealed an energetic phenotype with an increase in the oxygen consumption rate. The present findings demonstrate a novel function of KLHL3 mutation in extrarenal tissues, such as the liver, and may provide a therapeutic target against obesity and obesity-related diseases. Mice that are genetically engineered to lack a protein involved in regulating energy expenditure are protected against the onset of obesity and the related problems of insulin resistance and non-alcoholic fatty liver disease. Jeong-Ki Min, Jong-Gil Park and colleagues at the Korea Research Institute of Bioscience & Biotechnology in South Korea, Daejon, discovered that the beneficial effect of the lack of the protein, called KLHL3, was due to an increase in energy expenditure. Mutations in the gene for KLHL3 are known to cause a variety of metabolic diseases in humans, including a form of high blood pressure called Gordon’s hypertension syndrome, but the protein’s role in human obesity has not been studied. The results suggest that drugs able to regulate the production or activity of KLHL3 might offer a new approach to treating obesity.
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Affiliation(s)
- Ju-Hong Jang
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea.,Department of Bioscience, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Jeong Woong Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Min Ji Cho
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Byungtae Hwang
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Min-Gi Kwon
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea.,Department of Bioscience, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Dong-Hwan Kim
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Nam-Kyung Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Jangwook Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Young-Jun Park
- Environmental Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Yong Ryoul Yang
- Aging Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Jinchul Kim
- Aging Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Yong-Hoon Kim
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Tae Hyeon An
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Jong-Gil Park
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea. .,Department of Bioscience, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea.
| | - Jeong-Ki Min
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea. .,Department of Bioscience, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea.
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Collins KH, Gui C, Ely EV, Lenz KL, Harris CA, Guilak F, Meyer GA. Leptin mediates the regulation of muscle mass and strength by adipose tissue. J Physiol 2022; 600:3795-3817. [PMID: 35844058 PMCID: PMC9378542 DOI: 10.1113/jp283034] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 07/04/2022] [Indexed: 02/01/2023] Open
Abstract
Adipose tissue secretes numerous cytokines (termed 'adipokines') that have known or hypothesized actions on skeletal muscle. The majority of adipokines have been implicated in the pathological link between excess adipose and muscle insulin resistance, but approximately half also have documented in vitro effects on myogenesis and/or hypertrophy. This complexity suggests a potential dual role for adipokines in the regulation of muscle mass in homeostasis and the development of pathology. In this study, we used lipodystrophic 'fat-free' mice to demonstrate that adipose tissue is indeed necessary for the development of normal muscle mass and strength. Fat-free mice had significantly reduced mass (∼15%) and peak contractile tension (∼20%) of fast-twitch muscles, a slowing of contractile dynamics and decreased cross-sectional area of fast twitch fibres compared to wild-type littermates. These deficits in mass and contractile tension were fully rescued by reconstitution of ∼10% of normal adipose mass, indicating that this phenotype is the direct consequence of absent adipose. We then showed that the rescue is solely mediated by the adipokine leptin, as similar reconstitution of adipose from leptin-knockout mice fails to rescue mass or strength. Together, these data indicate that the development of muscle mass and strength in wild-type mice is dependent on adipose-secreted leptin. This finding extends our current understanding of the multiple roles of adipokines in physiology as well as disease pathophysiology to include a critical role for the adipokine leptin in muscle homeostasis. KEY POINTS: Adipose-derived cytokines (adipokines) have long been implicated in the pathogenesis of insulin resistance in obesity but likely have other under-appreciated roles in muscle physiology. Here we use a fat-free mouse to show that adipose tissue is necessary for the normal development of muscle mass and strength. Through add-back of genetically modified adipose tissue we show that leptin is the key adipokine mediating this regulation. This expands our understanding of leptin's role in adipose-muscle signalling to include development and homeostasis and adds the surprising finding that leptin is the sole mediator of the maintenance of muscle mass and strength by adipose tissue.
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Affiliation(s)
- Kelsey H. Collins
- Department of Orthopaedic SurgeryWashington University in St. LouisMOUSA,Shriners Hospitals for ChildrenSt LouisMOUSA,Center of Regenerative MedicineWashington University in St. LouisMOUSA
| | - Chang Gui
- Department of Biomedical EngineeringWashington University in St. LouisMOUSA,Program in Physical TherapyWashington UniversitySt LouisMOUSA
| | - Erica V. Ely
- Department of Orthopaedic SurgeryWashington University in St. LouisMOUSA,Shriners Hospitals for ChildrenSt LouisMOUSA,Center of Regenerative MedicineWashington University in St. LouisMOUSA,Department of Biomedical EngineeringWashington University in St. LouisMOUSA
| | - Kristin L. Lenz
- Department of Orthopaedic SurgeryWashington University in St. LouisMOUSA,Shriners Hospitals for ChildrenSt LouisMOUSA,Center of Regenerative MedicineWashington University in St. LouisMOUSA
| | - Charles A. Harris
- Division of EndocrinologyMetabolism & Lipid ResearchWashington UniversitySt LouisMissouriUSA
| | - Farshid Guilak
- Department of Orthopaedic SurgeryWashington University in St. LouisMOUSA,Shriners Hospitals for ChildrenSt LouisMOUSA,Center of Regenerative MedicineWashington University in St. LouisMOUSA,Department of Biomedical EngineeringWashington University in St. LouisMOUSA
| | - Gretchen A. Meyer
- Department of Orthopaedic SurgeryWashington University in St. LouisMOUSA,Center of Regenerative MedicineWashington University in St. LouisMOUSA,Department of Biomedical EngineeringWashington University in St. LouisMOUSA,Program in Physical TherapyWashington UniversitySt LouisMOUSA,Department of NeurologyWashington University in St. LouisSt LouisMOUSA
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Ghanbari M, Lamuki MS, Habibi E, Sadeghimahalli F. Artemisia annua L. Extracts Improved Insulin Resistance via Changing Adiponectin, Leptin and Resistin Production in HFD/STZ Diabetic Mice. J Pharmacopuncture 2022; 25:130-137. [PMID: 35837139 PMCID: PMC9240412 DOI: 10.3831/kpi.2022.25.2.130] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 02/17/2022] [Accepted: 04/04/2022] [Indexed: 11/17/2022] Open
Abstract
Objectives Insulin resistance (IR) is major cause of type 2 diabetes (T2D), and adipokines (e.g., adiponectin, leptin, and resistin) play an important role in insulin sensitivity. Medicinal plants are frequently used for T2D treatment. This study investigates the effect of Artemisia annua L. (AA) extracts on adipokines in mice with high-fat-diet (HFD)/streptozotocin (STZ)-induced T2D. Methods We divided 60 mice into 12 groups (n = 5 per group) control, untreated T2D, treated T2D, and 9 other groups. T2D was induced in all groups, except controls, by 8 weeks of HFD and STZ injection. The treated T2D group was administered 250 mg/kg of metformin (MTF), while the nine other groups were treated with 100, 200, and 400 mg/kg of hot-water extract (HWE), cold-water extract (CWE), and alcoholic extract (ALE) of AA (daily oral gavage) along with 250 mg/kg of MTF for 4 weeks. The intraperitoneal glucose tolerance test (IPGTT) was performed, and the homeostasis model assessment of adiponectin (HOMA-AD) index and blood glucose and serum insulin, leptin, adiponectin, and resistin levels were measured. Results Similar to MTF, all three types of AA extracts (HWEs, CWEs, and ALEs) significantly (p < 0.0001) decreased the area under the curve (AUC) of glucose during the IPGTT, the HOMA-AD index, blood glucose levels, and serum insulin, leptin, and resistin levels and increased serum adiponectin levels in the MTF group compared to the T2D group (p < 0.0001). The HWEs affected adipokine release, while the CWEs and ALEs decreased leptin and resistin production. Conclusion Water and alcoholic AA extracts have an antihyperglycemic and antihyperinsulinemic effect on HFD/STZ diabetic mice. In addition, they decrease IR by reducing leptin and resistin production and increasing adiponectin secretion from adipocytes.
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Affiliation(s)
- Mahshid Ghanbari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Manzandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Shokrzadeh Lamuki
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Manzandaran University of Medical Sciences, Sari, Iran
- Pharmaceutical Science Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Emran Habibi
- Pharmaceutical Science Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
- Department of Pharmacognosy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Forouzan Sadeghimahalli
- Pharmaceutical Science Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
- Department of Physiology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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Cacciottolo TM, Henning E, Keogh JM, Bel Lassen P, Lawler K, Bounds R, Ahmed R, Perdikari A, Mendes de Oliveira E, Smith M, Godfrey EM, Johnson E, Hodson L, Clément K, van der Klaauw AA, Farooqi IS. Obesity Due to Steroid Receptor Coactivator-1 Deficiency Is Associated With Endocrine and Metabolic Abnormalities. J Clin Endocrinol Metab 2022; 107:e2532-e2544. [PMID: 35137184 PMCID: PMC9113786 DOI: 10.1210/clinem/dgac067] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Genetic variants affecting the nuclear hormone receptor coactivator steroid receptor coactivator, SRC-1, have been identified in people with severe obesity and impair melanocortin signaling in cells and mice. As a result, obese patients with SRC-1 deficiency are being treated with a melanocortin 4 receptor agonist in clinical trials. OBJECTIVE Here, our aim was to comprehensively describe and characterize the clinical phenotype of SRC-1 variant carriers to facilitate diagnosis and clinical management. METHODS In genetic studies of 2462 people with severe obesity, we identified 23 rare heterozygous variants in SRC-1. We studied 29 adults and 18 children who were SRC-1 variant carriers and performed measurements of metabolic and endocrine function, liver imaging, and adipose tissue biopsies. Findings in adult SRC-1 variant carriers were compared to 30 age- and body mass index (BMI)-matched controls. RESULTS The clinical spectrum of SRC-1 variant carriers included increased food intake in children, normal basal metabolic rate, multiple fractures with minimal trauma (40%), persistent diarrhea, partial thyroid hormone resistance, and menorrhagia. Compared to age-, sex-, and BMI-matched controls, adult SRC-1 variant carriers had more severe adipose tissue fibrosis (46.2% vs 7.1% respectively, P = .03) and a suggestion of increased liver fibrosis (5/13 cases vs 2/13 in controls, odds ratio = 3.4), although this was not statistically significant. CONCLUSION SRC-1 variant carriers exhibit hyperphagia in childhood, severe obesity, and clinical features of partial hormone resistance. The presence of adipose tissue fibrosis and hepatic fibrosis in young patients suggests that close monitoring for the early development of obesity-associated metabolic complications is warranted.
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Affiliation(s)
- Tessa M Cacciottolo
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Elana Henning
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Julia M Keogh
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Pierre Bel Lassen
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics) Research Group and Assistance Publique hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - Katherine Lawler
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Rebecca Bounds
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Rachel Ahmed
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Aliki Perdikari
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Edson Mendes de Oliveira
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Miriam Smith
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Edmund M Godfrey
- Department of Radiology, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Elspeth Johnson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Headington, Oxford OX3 7LE, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Headington, Oxford OX3 7LE, UK
| | - Karine Clément
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics) Research Group and Assistance Publique hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - Agatha A van der Klaauw
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - I Sadaf Farooqi
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
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35
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Jouffe C, Weger BD, Martin E, Atger F, Weger M, Gobet C, Ramnath D, Charpagne A, Morin-Rivron D, Powell EE, Sweet MJ, Masoodi M, Uhlenhaut NH, Gachon F. Disruption of the circadian clock component BMAL1 elicits an endocrine adaption impacting on insulin sensitivity and liver disease. Proc Natl Acad Sci U S A 2022; 119:e2200083119. [PMID: 35238641 PMCID: PMC8916004 DOI: 10.1073/pnas.2200083119] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
SignificanceWhile increasing evidence associates the disruption of circadian rhythms with pathologic conditions, including obesity, type 2 diabetes, and nonalcoholic fatty liver diseases (NAFLD), the involved mechanisms are still poorly described. Here, we show that, in both humans and mice, the pathogenesis of NAFLD is associated with the disruption of the circadian clock combined with perturbations of the growth hormone and sex hormone pathways. However, while this condition protects mice from the development of fibrosis and insulin resistance, it correlates with increased fibrosis in humans. This suggests that the perturbation of the circadian clock and its associated disruption of the growth hormone and sex hormone pathways are critical for the pathogenesis of metabolic and liver diseases.
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Affiliation(s)
- Céline Jouffe
- Nestlé Research, Société des Produits Nestlé, CH-1015 Lausanne, Switzerland
- Department of Pharmacology and Toxicology, University of Lausanne, CH-1011 Lausanne, Switzerland
- Helmholtz Diabetes Center, Helmholtz Zentrum München, DE-85764 Neuherberg, Germany
| | - Benjamin D. Weger
- Nestlé Research, Société des Produits Nestlé, CH-1015 Lausanne, Switzerland
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Eva Martin
- Nestlé Research, Société des Produits Nestlé, CH-1015 Lausanne, Switzerland
| | - Florian Atger
- Nestlé Research, Société des Produits Nestlé, CH-1015 Lausanne, Switzerland
- Department of Pharmacology and Toxicology, University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Meltem Weger
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Cédric Gobet
- Nestlé Research, Société des Produits Nestlé, CH-1015 Lausanne, Switzerland
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Divya Ramnath
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Aline Charpagne
- Nestlé Research, Société des Produits Nestlé, CH-1015 Lausanne, Switzerland
| | | | - Elizabeth E. Powell
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane QLD 4102, Australia
- Faculty of Medicine, Center for Liver Disease Research, Translational Research Institute, The University of Queensland, Brisbane QLD 4102, Australia
| | - Matthew J. Sweet
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Mojgan Masoodi
- Nestlé Research, Société des Produits Nestlé, CH-1015 Lausanne, Switzerland
- Institute of Clinical Chemistry, Bern University Hospital, Bern 3010, Switzerland
| | - N. Henriette Uhlenhaut
- Helmholtz Diabetes Center, Helmholtz Zentrum München, DE-85764 Neuherberg, Germany
- Metabolic Programming, Technical University of Munich School of Life Sciences, DE-85354 Freising, Germany
| | - Frédéric Gachon
- Nestlé Research, Société des Produits Nestlé, CH-1015 Lausanne, Switzerland
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
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36
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Kamstra K, Rizwan MZ, Grattan DR, Horsfield JA, Tups A. Leptin regulates glucose homeostasis via the canonical Wnt pathway in the zebrafish. FASEB J 2022; 36:e22207. [PMID: 35188286 DOI: 10.1096/fj.202101764r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/12/2022] [Accepted: 02/01/2022] [Indexed: 11/11/2022]
Abstract
Leptin is best known for its role in adipostasis, but it also regulates blood glucose levels. The molecular mechanism by which leptin controls glucose homeostasis remains largely unknown. Here, we use a zebrafish model to show that Wnt signaling mediates the glucoregulatory effects of leptin. Under normal feeding conditions, leptin regulates glucose homeostasis but not adipostasis in zebrafish. In times of nutrient excess, however, we found that leptin also regulates body weight and size. Using a Wnt signaling reporter fish, we show that leptin activates the canonical Wnt pathway in vivo. Utilizing two paradigms for hyperglycemia, it is revealed that leptin regulates glucose homeostasis via the Wnt pathway, as pharmacological inhibition of this pathway impairs the glucoregulatory actions of leptin. Our results may shed new light on the evolution of the physiological function of leptin.
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Affiliation(s)
- Kaj Kamstra
- Centre for Neuroendocrinology and Brain Health Research Centre, University Otago, Dunedin, New Zealand.,Department of Physiology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Mohammed Z Rizwan
- Centre for Neuroendocrinology and Brain Health Research Centre, University Otago, Dunedin, New Zealand.,Department of Anatomy, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - David R Grattan
- Centre for Neuroendocrinology and Brain Health Research Centre, University Otago, Dunedin, New Zealand.,Department of Anatomy, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Julia A Horsfield
- Department of Pathology, University of Otago, Dunedin, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Alexander Tups
- Centre for Neuroendocrinology and Brain Health Research Centre, University Otago, Dunedin, New Zealand.,Department of Physiology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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37
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Toyoda S, Shin J, Fukuhara A, Otsuki M, Shimomura I. Transforming growth factor β1 signaling links extracellular matrix remodeling to intracellular lipogenesis upon physiological feeding events. J Biol Chem 2022; 298:101748. [PMID: 35189145 PMCID: PMC8931428 DOI: 10.1016/j.jbc.2022.101748] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue dynamically changes its mass in response to external nutritional status, which plays an important role in maintaining the lipid homeostasis. Physiologically, feeding events are associated with the expansion of adipose tissue, but little is known about the detailed molecular mechanisms of this expansion. Here, using comprehensive transcriptome analysis, we found that levels of transforming growth factor β1 (TGF-β1), a key regulator of extracellular matrix (ECM) remodeling, were increased in adipose tissue under feeding conditions and associated with the lipogenic pathway. In addition, TGF-β receptors are highly expressed in adipose tissue, and pharmacological inhibition of TGF-β1 reduced adipose tissue mass and caused ectopic lipid accumulation in the liver. This reduced fat mass was associated with decreased gene expression in ECM remodeling and lipogenesis. Furthermore, similar results were observed in the adipose tissue of SMAD family member 3 knockout mice or upon systemic TGF-β neutralization, with significant reductions in both ECM remodeling and lipogenesis-related genes. Mechanistically, we found that insulin-induced TGF-β1 and cell-autonomous action remodels the ECM of adipocytes, which controls the downstream focal adhesion kinase–AKT signaling cascades and enhances the lipogenic pathway. Of note, destruction of collagens or matrix metalloproteinase/a disintegrin and metalloprotease activities, critical components of ECM remodeling, blocked TGF-β1-mediated focal adhesion kinase–AKT signaling and the lipogenic pathway. Taken together, this study identifies a previously unknown lipogenic role of TGF-β1 by which adipocytes can expand to adapt to physiological feeding events.
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Affiliation(s)
- Shinichiro Toyoda
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Jihoon Shin
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Diabetes Care Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
| | - Atsunori Fukuhara
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Adipose Management, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Michio Otsuki
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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38
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Chai BK, Murugan DD, Rais MM, Al-Shagga M, Mohankumar SK. Conjugated linoleic acid isomers induced dyslipidemia and lipoatrophy are exacerbated by rosiglitazone in ApoE null mice fed a Western diet. MEDITERRANEAN JOURNAL OF NUTRITION AND METABOLISM 2022. [DOI: 10.3233/mnm-211562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND: Insulin sensitizers have been used to treat Type 2 diabetes. However, their non-negligible side effects have led to cardiovascular concerns and the withdrawal of a member, rosiglitazone. OBJECTIVE: We combined conjugated linoleic acid (CLA) with rosiglitazone to test for amelioration of side effects posed by rosiglitazone in vivo. METHODS: We utilized ApoE null mice fed with Western diet (WD) to test our hypothesis. Mice were fed WD, with or without CLA administration, for 12 weeks. CLA utilized in our study consisted of a 1:1 ratio of 95% pure c9,t11, and t10,c12 isomers at a concentration of 0.1% w/v in fat-free milk. Starting from Week 12, select mice received rosiglitazone. RESULTS: It was found that mice receiving CLA from Week 0 and rosiglitazone from Week 12 had the lowest body weight and exacerbated hepatomegaly. Although these mice had attenuated insulin resistance compared to mice receiving only Western diet, they display a marked increase in total plasma cholesterol and low-density lipoprotein (LDL) cholesterol. Mice receiving early CLA administration developed hyperleptinemia, which was not restored by rosiglitazone. CONCLUSION: Taken together, against the background of ApoE null genotype and WD feeding, simultaneous administration of 1:1 CLA and rosiglitazone led to dyslipidemic lipoatrophy.
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Affiliation(s)
- Boon Kheng Chai
- Division of Biomedical Sciences, Faculty ofScience, University of Nottingham Malaysia Campus, Jalan Broga, Semenyih, Selangor Darul Ehsan, Malaysia
- Present address: Biomedical Translation Research Centre, National Biotechnology Research Park, No 99, Lane 130, Academia Road Section 1, Nangang District, Taipei City 11571, Taiwan
| | - Dharmani Devi Murugan
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Mustafa Mohd Rais
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Mustafa Al-Shagga
- Division of Biomedical Sciences, Faculty ofScience, University of Nottingham Malaysia Campus, Jalan Broga, Semenyih, Selangor Darul Ehsan, Malaysia
| | - Suresh K. Mohankumar
- Division of Biomedical Sciences, Faculty ofScience, University of Nottingham Malaysia Campus, Jalan Broga, Semenyih, Selangor Darul Ehsan, Malaysia
- Present address: Swansea University Medical School, Singleton Park, Swansea SA2 8PP, Wales, United Kingdom
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Simha V, Lanza IR, Dasari S, Klaus KA, Le Brasseur N, Vuckovic I, Laurenti MC, Cobelli C, Port JD, Nair KS. Impaired Muscle Mitochondrial Function in Familial Partial Lipodystrophy. J Clin Endocrinol Metab 2022; 107:346-362. [PMID: 34614176 PMCID: PMC8764358 DOI: 10.1210/clinem/dgab725] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Indexed: 01/04/2023]
Abstract
CONTEXT Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known. OBJECTIVE To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences. METHODS Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis. RESULTS Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed. CONCLUSION Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects.
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MESH Headings
- Absorptiometry, Photon
- Adult
- Aged
- Female
- Gene Expression Profiling
- Humans
- Lipodystrophy, Familial Partial/genetics
- Lipodystrophy, Familial Partial/metabolism
- Lipodystrophy, Familial Partial/pathology
- Lipodystrophy, Familial Partial/physiopathology
- Male
- Middle Aged
- Mitochondria, Muscle/metabolism
- Mitochondria, Muscle/pathology
- Muscle Strength/physiology
- Muscle, Skeletal/cytology
- Muscle, Skeletal/pathology
- Muscle, Skeletal/physiopathology
- Physical Endurance/physiology
- Proteolysis
- Young Adult
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Affiliation(s)
- Vinaya Simha
- Divisions of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA
| | - Ian R Lanza
- Divisions of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA
| | - Surendra Dasari
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Nathan Le Brasseur
- Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA
| | - Ivan Vuckovic
- Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | | | | | - John D Port
- Radiology, Mayo Clinic, Rochester, MN 55905, USA
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40
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Mainieri F, Tagi VM, Chiarelli F. Treatment Options for Lipodystrophy in Children. Front Endocrinol (Lausanne) 2022; 13:879979. [PMID: 35600578 PMCID: PMC9114741 DOI: 10.3389/fendo.2022.879979] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 03/31/2022] [Indexed: 11/25/2022] Open
Abstract
Lipodystrophy includes a heterogeneous group of rare diseases characterized by different amounts of adipose tissue loss and several metabolic complications, including hypertriglyceridemia, steatohepatitis and particularly insulin resistance, that may lead to severe morbidity and, sometimes, mortality. Therefore, therapy for lipodystrophy primarily consists of a conventional approach that involves standard treatments of metabolic abnormalities. Given the evidence of leptin deficiency in lipodystrophy syndromes, leptin replacement therapy has been considered as a treatment option. Long-term studies on the use of therapy with a methionylated analog of human leptin, metreleptin, first on animals and subsequently on human patients, demonstrated enormous improvements of patients' clinical features and metabolic conditions. Recently, metreleptin was approved by Food and Drug Administration (FDA) for the treatment of generalized lipodystrophy and by European Medicines Agency (EMA) for the treatment of both generalized and partial lipodystrophy. However, further research is being conducted for new and different therapeutic agents, especially helpful for the treatment of patients with partial lipodystrophy, as some of them do not have access to metreleptin therapy or show poor response.
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41
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Le Lay S, Magré J, Prieur X. Not Enough Fat: Mouse Models of Inherited Lipodystrophy. Front Endocrinol (Lausanne) 2022; 13:785819. [PMID: 35250856 PMCID: PMC8895270 DOI: 10.3389/fendo.2022.785819] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/17/2022] [Indexed: 12/19/2022] Open
Abstract
Lipodystrophies belong to the heterogenous group of syndromes in which the primary defect is a generalized or partial absence of adipose tissue, which may be congenital or acquired in origin. Lipodystrophy should be considered in patients manifesting the combination of insulin resistance (with or without overt diabetes), dyslipidemia and fatty liver. Lipodystrophies are classified according to the etiology of the disease (genetic or acquired) and to the anatomical distribution of adipose tissue (generalized or partial). The mechanism of adipose tissue loss is specific to each syndrome, depending on the biological function of the mutated gene. Mice models, together with cellular studies have permitted clarification of the mechanisms by which human mutations deeply compromise adipocyte homeostasis. In addition, rodent models have proven to be crucial in deciphering the cardiometabolic consequences of the lack of adipose tissue such as NAFLD, muscle insulin resistance and cardiomyopathy. More precisely, tissue-specific transgenic and knockout mice have brought new tools to distinguish phenotypic traits that are the consequences of lipodystrophy from those that are cell-autonomous. In this review, we discuss the mice models of lipodystrophy including those of inherited human syndromes of generalized and partial lipodystrophy. We present how these models have demonstrated the central role of white adipose tissue in energetic homeostasis in general, including insulin sensitivity and lipid handling in particular. We underscore the differences reported with the human phenotype and discuss the limit of rodent models in recapitulating adipose tissue primary default. Finally, we present how these mice models have highlighted the function of the causative-genes and brought new insights into the pathophysiology of the cardiometabolic complications associated with lipodystrophy.
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Affiliation(s)
- Soazig Le Lay
- Nantes Université, CNRS, INSERM, l’institut du thorax, Nantes, France
- Univ Angers, SFR ICAT, Angers, France
| | - Jocelyne Magré
- Nantes Université, CNRS, INSERM, l’institut du thorax, Nantes, France
| | - Xavier Prieur
- Nantes Université, CNRS, INSERM, l’institut du thorax, Nantes, France
- *Correspondence: Xavier Prieur,
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42
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Zhang L, Zhao J, Mu X, McGowan SJ, Angelini L, O'Kelly RD, Yousefzadeh MJ, Sakamoto A, Aversa Z, LeBrasseur NK, Suh Y, Huard J, Kamenecka TM, Niedernhofer LJ, Robbins PD. Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging. Aging Cell 2021; 20:e13486. [PMID: 34734460 PMCID: PMC8672781 DOI: 10.1111/acel.13486] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 09/01/2021] [Accepted: 09/13/2021] [Indexed: 11/30/2022] Open
Abstract
Constitutive NF-κB activation is associated with cellular senescence and stem cell dysfunction and rare variants in NF-κB family members are enriched in centenarians. We recently identified a novel small molecule (SR12343) that inhibits IKK/NF-κB activation by disrupting the association between IKKβ and NEMO. Here we investigated the therapeutic effects of SR12343 on senescence and aging in three different mouse models. SR12343 reduced senescence-associated beta-galactosidase (SA-β-gal) activity in oxidative stress-induced senescent mouse embryonic fibroblasts as well as in etoposide-induced senescent human IMR90 cells. Chronic administration of SR12343 to the Ercc1-/∆ and Zmpste24-/- mouse models of accelerated aging reduced markers of cellular senescence and SASP and improved multiple parameters of aging. SR12343 also reduced markers of senescence and increased muscle fiber size in 2-year-old WT mice. Taken together, these results demonstrate that IKK/NF-κB signaling pathway represents a promising target for reducing markers of cellular senescence, extending healthspan and treating age-related diseases.
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Affiliation(s)
- Lei Zhang
- Department of Biochemistry, Molecular Biology and BiophysicsInstitute on the Biology of Aging and MetabolismUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Jing Zhao
- Department of Molecular MedicineScripps ResearchJupiterFloridaUSA
| | - Xiaodong Mu
- Center for Regenerative Sports MedicineSteadman Philippon Research InstituteVailColoradoUSA
- Shandong First Medical University (Shandong Academy of Medical Sciences)JinanChina
| | - Sara J. McGowan
- Department of Biochemistry, Molecular Biology and BiophysicsInstitute on the Biology of Aging and MetabolismUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Luise Angelini
- Department of Biochemistry, Molecular Biology and BiophysicsInstitute on the Biology of Aging and MetabolismUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Ryan D. O'Kelly
- Department of Biochemistry, Molecular Biology and BiophysicsInstitute on the Biology of Aging and MetabolismUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Matthew J. Yousefzadeh
- Department of Biochemistry, Molecular Biology and BiophysicsInstitute on the Biology of Aging and MetabolismUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Ayumi Sakamoto
- Department of Physical Medicine and Rehabilitation and Robert and Arlene Kogod Center on AgingRochesterMinnesotaUSA
| | - Zaira Aversa
- Department of Physical Medicine and Rehabilitation and Robert and Arlene Kogod Center on AgingRochesterMinnesotaUSA
| | - Nathan K. LeBrasseur
- Department of Physical Medicine and Rehabilitation and Robert and Arlene Kogod Center on AgingRochesterMinnesotaUSA
| | - Yousin Suh
- Department of Genetics and DevelopmentColumbia UniversityNew YorkNew YorkUSA
| | - Johnny Huard
- Center for Regenerative Sports MedicineSteadman Philippon Research InstituteVailColoradoUSA
| | | | - Laura J. Niedernhofer
- Department of Biochemistry, Molecular Biology and BiophysicsInstitute on the Biology of Aging and MetabolismUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Paul D. Robbins
- Department of Biochemistry, Molecular Biology and BiophysicsInstitute on the Biology of Aging and MetabolismUniversity of MinnesotaMinneapolisMinnesotaUSA
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Zhang D, Zhu H, Zhan E, Wang F, Liu Y, Xu W, Liu X, Liu J, Li S, Pan Y, Wang Y, Cao W. Vaspin Mediates the Intraorgan Crosstalk Between Heart and Adipose Tissue in Lipoatrophic Mice. Front Cell Dev Biol 2021; 9:647131. [PMID: 34631690 PMCID: PMC8497826 DOI: 10.3389/fcell.2021.647131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 09/01/2021] [Indexed: 11/13/2022] Open
Abstract
Lipoatrophy is characterized as selective loss of adipose tissues, leading to the severity of cardiovascular disorders. Therefore, there was close intraorgan crosstalk between adipose tissue and cardiovascular in lipoatrophy. A-ZIP/F-1 mouse, a well-established lipoatrophic model, and primary cardiomyocytes were used for investigating the pathophysiological changes and molecular mechanisms. A-ZIP/F-1 mice had severe fat loss and impaired ventricular function during growth, but closely associated with the reduction of circulating vaspin levels. Administration of recombinant vaspin protein improved cardiac structural disorders, left ventricular dysfunction, and inflammatory response in lipoatrophic mice. In detail, vaspin decreased cardiac lipid deposits, but enhanced mitochondrial biogenesis and activities. Interestingly, A-ZIP/F-1 mice transplanted with normal visceral adipose tissues exhibited improvement in cardiac structural remodeling and mitochondrial function. Mechanistically, vaspin increased cardiac AKT activity, which guaranteed the mitochondrial benefits of vaspin in lipoatrophic mice and primary mouse cardiomyocytes. The present study suggested that vaspin possessed biological benefits in attenuating lipoatrophy-induced cardiomyopathy onset, and targeting vaspin/AKT signaling was a potential strategy to maintain heart metabolism.
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Affiliation(s)
- Donghui Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Hong Zhu
- Department of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Enbo Zhan
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Fan Wang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Yue Liu
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wei Xu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Xian Liu
- Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jingjin Liu
- Department of Cardiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Shufeng Li
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Yong Pan
- Department of Pathophysiology, Shenzhen University, Shenzhen, China.,Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention, Shenzhen, Guang Dong, China
| | - Yongshun Wang
- Department of Cardiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Wei Cao
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
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Reduced Endothelial Leptin Signaling Increases Vascular Adrenergic Reactivity in a Mouse Model of Congenital Generalized Lipodystrophy. Int J Mol Sci 2021; 22:ijms221910596. [PMID: 34638939 PMCID: PMC8508873 DOI: 10.3390/ijms221910596] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/20/2021] [Accepted: 09/27/2021] [Indexed: 01/19/2023] Open
Abstract
The adipokine leptin, which is best-known for its role in the control of metabolic function, is also a master regulator of cardiovascular function. While leptin has been approved for the treatment of metabolic disorders in patients with congenital generalized lipodystrophy (CGL), the effects of chronic leptin deficiency and the treatment on vascular contractility remain unknown. Herein, we investigated the effects of leptin deficiency and treatment (0.3 mg/day/7 days) on aortic contractility in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-, model of CGL) and their wild-type control (gBscl2+/+), as well as in mice with selective deficiency in endothelial leptin receptor (LepREC-/-). Lipodystrophy selectively increased vascular adrenergic contractility via NO-independent mechanisms and induced hypertrophic vascular remodeling. Leptin treatment and Nox1 inhibition blunted adrenergic hypercontractility in gBscl2-/- mice, however, leptin failed to rescue vascular media thickness. Selective deficiency in endothelial leptin receptor did not alter baseline adrenergic contractility but abolished leptin-mediated reduction in adrenergic contractility, supporting the contribution of endothelium-dependent mechanisms. These data reveal a new direct role for endothelial leptin receptors in the control of vascular contractility and homeostasis, and present leptin as a safe therapy for the treatment of vascular disease in CGL.
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Abstract
Lipodystrophy syndromes (LS) constitute a group of rare diseases of the adipose tissue, characterized by a complete or selective deficiency of the fat mass. These disorders are associated with important insulin resistance, cardiovascular and metabolic comorbidities that impact patient's survival and quality of life. Management is challenging and includes diet, physical activity, and specific pharmacological treatment of LS-associated comorbidities. Because of a common pathophysiology involving decreased concentration of the adipokine leptin, efforts have been made to develop therapeutic strategies with leptin replacement therapy. Metreleptin, a recombinant human leptin analogue, has been proposed in hypoleptinemic patients since the beginning of 2000's. The treatment leads to an improvement in metabolic parameters, more important in generalized than in partial LS forms. In this review, the current knowledge about the development of the drug, its outcomes in the treatment of lipodystrophic patients as well as the peculiarities of its use will be presented.
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Corsa CAS, Walsh CM, Bagchi DP, Foss Freitas MC, Li Z, Hardij J, Granger K, Mori H, Schill RL, Lewis KT, Maung JN, Azaria RD, Rothberg AE, Oral EA, MacDougald OA. Adipocyte-Specific Deletion of Lamin A/C Largely Models Human Familial Partial Lipodystrophy Type 2. Diabetes 2021; 70:1970-1984. [PMID: 34088712 PMCID: PMC8576431 DOI: 10.2337/db20-1001] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 05/25/2021] [Indexed: 11/13/2022]
Abstract
Mechanisms by which autosomal recessive mutations in Lmna cause familial partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate the function of lamin A/C in adipose tissue, we created mice with an adipocyte-specific loss of Lmna (Lmna ADKO). Although Lmna ADKO mice develop and maintain adipose tissues in early postnatal life, they show a striking and progressive loss of white and brown adipose tissues as they approach sexual maturity. Lmna ADKO mice exhibit surprisingly mild metabolic dysfunction on a chow diet, but on a high-fat diet they share many characteristics of FPLD2 including hyperglycemia, hepatic steatosis, hyperinsulinemia, and almost undetectable circulating adiponectin and leptin. Whereas Lmna ADKO mice have reduced regulated and constitutive bone marrow adipose tissue with a concomitant increase in cortical bone, FPLD2 patients have reduced bone mass and bone mineral density compared with controls. In cell culture models of Lmna deficiency, mesenchymal precursors undergo adipogenesis without impairment, whereas fully differentiated adipocytes have increased lipolytic responses to adrenergic stimuli. Lmna ADKO mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying Lmna-dependent loss of adipose tissues.
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Affiliation(s)
- Callie A S Corsa
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Carolyn M Walsh
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Devika P Bagchi
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Maria C Foss Freitas
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Ziru Li
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Julie Hardij
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Katrina Granger
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Hiroyuki Mori
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Rebecca L Schill
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Kenneth T Lewis
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Jessica N Maung
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Ruth D Azaria
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Amy E Rothberg
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Elif A Oral
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Ormond A MacDougald
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
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Amatruda M, Gembillo G, Giuffrida AE, Santoro D, Conti G. The Aggressive Diabetic Kidney Disease in Youth-Onset Type 2 Diabetes: Pathogenetic Mechanisms and Potential Therapies. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:868. [PMID: 34577791 PMCID: PMC8467670 DOI: 10.3390/medicina57090868] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 02/07/2023]
Abstract
Youth-onset Type 2 Diabetes Mellitus (T2DM) represents a major burden worldwide. In the last decades, the prevalence of T2DM became higher than that of Type 1 Diabetes Mellitus (T1DM), helped by the increasing rate of childhood obesity. The highest prevalence rates of youth-onset T2DM are recorded in China (520 cases/100,000) and in the United States (212 cases/100,000), and the numbers are still increasing. T2DM young people present a strong hereditary component, often unmasked by social and environmental risk factors. These patients are affected by multiple coexisting risk factors, including obesity, hyperglycemia, dyslipidemia, insulin resistance, hypertension, and inflammation. Juvenile T2DM nephropathy occurs earlier in life compared to T1DM-related nephropathy in children or T2DM-related nephropathy in adult. Diabetic kidney disease (DKD) is T2DM major long term microvascular complication. This review summarizes the main mechanisms involved in the pathogenesis of the DKD in young population and the recent evolution of treatment, in order to reduce the risk of DKD progression.
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Affiliation(s)
- Michela Amatruda
- Unit of Pediatric Nephrology with Dialysis, AOU Policlinic G Martino, University of Messina, 98125 Messina, Italy;
| | - Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
- Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, 98125 Messina, Italy
| | - Alfio Edoardo Giuffrida
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
| | - Giovanni Conti
- Unit of Pediatric Nephrology with Dialysis, AOU Policlinic G Martino, University of Messina, 98125 Messina, Italy;
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Hoffmann A, Ebert T, Hankir MK, Flehmig G, Klöting N, Jessnitzer B, Lössner U, Stumvoll M, Blüher M, Fasshauer M, Tönjes A, Miehle K, Kralisch S. Leptin Improves Parameters of Brown Adipose Tissue Thermogenesis in Lipodystrophic Mice. Nutrients 2021; 13:2499. [PMID: 34444659 PMCID: PMC8399124 DOI: 10.3390/nu13082499] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/16/2021] [Accepted: 07/18/2021] [Indexed: 12/18/2022] Open
Abstract
Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.
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Affiliation(s)
- Annett Hoffmann
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany; (T.E.); (G.F.); (B.J.); (U.L.); (M.S.); (M.B.); (A.T.); (K.M.); (S.K.)
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, 97080 Würzburg, Germany;
| | - Thomas Ebert
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany; (T.E.); (G.F.); (B.J.); (U.L.); (M.S.); (M.B.); (A.T.); (K.M.); (S.K.)
- Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 17177 Solna, Sweden
| | - Mohammed K. Hankir
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, 97080 Würzburg, Germany;
| | - Gesine Flehmig
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany; (T.E.); (G.F.); (B.J.); (U.L.); (M.S.); (M.B.); (A.T.); (K.M.); (S.K.)
| | - Nora Klöting
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, 04109 Leipzig, Germany;
| | - Beate Jessnitzer
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany; (T.E.); (G.F.); (B.J.); (U.L.); (M.S.); (M.B.); (A.T.); (K.M.); (S.K.)
| | - Ulrike Lössner
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany; (T.E.); (G.F.); (B.J.); (U.L.); (M.S.); (M.B.); (A.T.); (K.M.); (S.K.)
| | - Michael Stumvoll
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany; (T.E.); (G.F.); (B.J.); (U.L.); (M.S.); (M.B.); (A.T.); (K.M.); (S.K.)
| | - Matthias Blüher
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany; (T.E.); (G.F.); (B.J.); (U.L.); (M.S.); (M.B.); (A.T.); (K.M.); (S.K.)
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, 04109 Leipzig, Germany;
| | - Mathias Fasshauer
- Institute of Nutritional Science, Justus-Liebig-University, 35390 Giessen, Germany;
| | - Anke Tönjes
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany; (T.E.); (G.F.); (B.J.); (U.L.); (M.S.); (M.B.); (A.T.); (K.M.); (S.K.)
| | - Konstanze Miehle
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany; (T.E.); (G.F.); (B.J.); (U.L.); (M.S.); (M.B.); (A.T.); (K.M.); (S.K.)
| | - Susan Kralisch
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany; (T.E.); (G.F.); (B.J.); (U.L.); (M.S.); (M.B.); (A.T.); (K.M.); (S.K.)
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Akinci B, Subauste A, Ajluni N, Esfandiari NH, Meral R, Neidert AH, Eraslan A, Hench R, Rus D, Mckenna B, Hussain HK, Chenevert TL, Tayeh MK, Rupani AR, Innis JW, Mantzoros CS, Conjeevaram HS, Burant CL, Oral EA. Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings. MED 2021; 2:814-835. [DOI: 10.1016/j.medj.2021.04.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Barbu E, Popescu MR, Popescu AC, Balanescu SM. Phenotyping the Prediabetic Population-A Closer Look at Intermediate Glucose Status and Cardiovascular Disease. Int J Mol Sci 2021; 22:6864. [PMID: 34202289 PMCID: PMC8268766 DOI: 10.3390/ijms22136864] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 06/12/2021] [Accepted: 06/17/2021] [Indexed: 01/08/2023] Open
Abstract
Even though the new thresholds for defining prediabetes have been around for more than ten years, there is still controversy surrounding the precise characterization of this intermediate glucose metabolism status. The risk of developing diabetes and macro and microvascular disease linked to prediabetes is well known. Still, the prediabetic population is far from being homogenous, and phenotyping it into less heterogeneous groups might prove useful for long-term risk assessment, follow-up, and primary prevention. Unfortunately, the current definition of prediabetes is quite rigid and disregards the underlying pathophysiologic mechanisms and their potential metabolic progression towards overt disease. In addition, prediabetes is commonly associated with a cluster of risk factors that worsen the prognosis. These risk factors all revolve around a common denominator: inflammation. This review focuses on identifying the population that needs to be screened for prediabetes and the already declared prediabetic patients who are at a higher risk of cardiovascular disease and require closer monitoring.
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Affiliation(s)
| | - Mihaela-Roxana Popescu
- Department of Cardiology, Elias Emergency University Hospital, Carol Davila University of Medicine and Pharmacy, 011461 Bucharest, Romania; (E.B.); (S.-M.B.)
| | - Andreea-Catarina Popescu
- Department of Cardiology, Elias Emergency University Hospital, Carol Davila University of Medicine and Pharmacy, 011461 Bucharest, Romania; (E.B.); (S.-M.B.)
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