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Yaligar J, Rengaraj A, Le GTT, Leow MKS, Eriksson JG, Ashokkumar B, Velan SS. Fatty Acylcarnitine Metabolism in Brown/Beige and White Fats by 13C HRMAS NMR Spectroscopy With Metabolic Interventions. NMR IN BIOMEDICINE 2025; 38:e70040. [PMID: 40230060 DOI: 10.1002/nbm.70040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/24/2025] [Accepted: 03/26/2025] [Indexed: 04/16/2025]
Abstract
White adipose tissue (WAT) and brown adipose tissue (BAT) have distinct structural and physiological characteristics and serve opposing functions in the body. WAT primarily stores energy, whereas BAT is metabolically active and positively influences metabolic health, contributing to energy expenditure, reduced fat accumulation and enhanced mitochondrial metabolism. Recently, both classical BAT and beige fat (or inducible/recruitable BAT) that arises from the browning of WAT have attracted clinical interest as potential targets for improving mitochondrial metabolism and managing obesity-related metabolic disorders. Currently, there is a lack of specific metabolic biomarkers for characterizing classical BAT and beige fat tissues, which are essential for evaluating mitochondrial oxidative metabolism and screening browning agents for therapeutic use. In this study, we investigated the potential metabolic biomarker fatty acylcarnitine in interscapular BAT (iBAT) from the interscapular region and beige adipose tissue from the inguinal region of the animal using ex vivo 13C high-resolution magic angle spinning (HRMAS) NMR spectroscopy. We examined how mitochondrial oxidative metabolism was altered in response to a high-fat diet (HFD) and how it was restored through iBAT activation using stimuli such as cold exposure and β3-adrenergic receptor (β3-AR) agonist, CL-316,243 treatment. We identified fatty acylcarnitine as a potential metabolic marker present in iBAT and beige tissues, whereas it was absent in iWAT. The concentration of fatty acylcarnitine significantly decreased in HFD-fed animals due to impaired lipolysis resulting in inefficient shuttling of fatty acids for mitochondrial β oxidation. However, its concentration increased or was restored in response to iBAT activation through either β3-AR agonist treatment or cold exposure, indicating a high-energy metabolic state with enhanced mitochondrial metabolism in iBAT. Fatty acylcarnitine shows promise as a biomarker for evaluating mitochondrial metabolism and for screening potential browning agents and nutraceuticals capable of inducing the browning of WAT.
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Affiliation(s)
- Jadegoud Yaligar
- Institute for Human Development and Potential, Agency for Science Technology and Research (A*STAR), Singapore
- Laboratory of Molecular Imaging, Institute of Bioengineering and Bioimaging, A*STAR, Singapore
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Anantharaj Rengaraj
- Institute for Human Development and Potential, Agency for Science Technology and Research (A*STAR), Singapore
- Laboratory of Molecular Imaging, Institute of Bioengineering and Bioimaging, A*STAR, Singapore
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, India
| | - Giang Thi Thu Le
- Institute for Human Development and Potential, Agency for Science Technology and Research (A*STAR), Singapore
- Laboratory of Molecular Imaging, Institute of Bioengineering and Bioimaging, A*STAR, Singapore
| | - Melvin Khee-Shing Leow
- Institute for Human Development and Potential, Agency for Science Technology and Research (A*STAR), Singapore
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
- Cardiovascular and Metabolic Diseases Program, Duke-NUS Medical School, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Medicine, Department of Endocrinology, Tan Tock Seng Hospital, Singapore
| | - Johan G Eriksson
- Institute for Human Development and Potential, Agency for Science Technology and Research (A*STAR), Singapore
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - S Sendhil Velan
- Institute for Human Development and Potential, Agency for Science Technology and Research (A*STAR), Singapore
- Laboratory of Molecular Imaging, Institute of Bioengineering and Bioimaging, A*STAR, Singapore
- Human Magnetic Resonance Centre, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts, USA
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Wang J, He Y, Kim AR, Lee KH, Choi SW. Effects of different types of exercise on inflammatory markers in cancer patients: A systematic review and Bayesian network meta-analysis. J Sports Sci 2025; 43:1121-1138. [PMID: 40197224 DOI: 10.1080/02640414.2025.2486886] [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: 12/01/2024] [Accepted: 03/23/2025] [Indexed: 04/10/2025]
Abstract
This systematic review and network meta-analysis (NMA) was to investigate the effects of different exercise modalities on inflammatory markers in cancer patients. Using the standardized mean difference (SMD) as the effect size, a Bayesian random-effects network meta-analysis and regression analysis were conducted. Searches were performed across five databases for randomized controlled trials (RCTs) involving cancer patients, with exercise as the intervention, reported outcomes related to inflammatory markers, and interventions lasting more than four weeks, up to June 2024. A total of 57 RCTs (3106 patients) were included. The Cochrane risk of Bias Tool was utilized to assess the RCTs, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was employed to evaluate the quality of evidence. NMA results indicate that regular exercise is effective in reducing inflammation in cancer patients, with combined high-intensity aerobic and resistance exercises proving to be the most beneficial. The type, intensity, and total volume of exercise are critical factors in achieving positive outcomes. It is recommended to design exercise programs for cancer patients that combine aerobic and resistance training, with a gradual increase in intensity to ensure safety.
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Affiliation(s)
- Jingyu Wang
- Department of Sport Leisure, Sungshin Women's University, Seoul, Republic of Korea
| | - Yuxuan He
- Department of Sport Leisure, Sungshin Women's University, Seoul, Republic of Korea
- College of Education, GongQing Institute of Science and Technology, Jiujiang, China
| | - A-Ram Kim
- Department of Sport Leisure, Sungshin Women's University, Seoul, Republic of Korea
| | - Kyung-Hee Lee
- Department of Exercise Therapy, Gachon University, Seoul, Republic of Korea
| | - Seung-Wook Choi
- Department of Sport Leisure, Sungshin Women's University, Seoul, Republic of Korea
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Flori L, Galgani G, Bray G, Ippolito C, Segnani C, Pellegrini C, Citi V, Bernardini N, Martelli A, Calderone V. Development of an adipocyte differentiation protocol using 3T3-L1 cells for the investigation of the browning process: identification of the PPAR-γ agonist rosiglitazone as a browning reference drug. Front Pharmacol 2025; 16:1546456. [PMID: 40297148 PMCID: PMC12034677 DOI: 10.3389/fphar.2025.1546456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 03/17/2025] [Indexed: 04/30/2025] Open
Abstract
Background Obesity is a metabolic disease that is characterized by an excessive accumulation of adipose tissue (AT) and is often associated with other pathologies. AT is a lipid storage organ with endocrine functions that presents two main phenotypes: white adipose tissue (WAT) and brown adipose tissue (BAT). Preadipocytes or mature white adipocyte cells can differentiate in a middle phenotype with morpho/functional characteristics between WAT and BAT, known as brown-like or beige adipose tissue (BeAT), through the browning process. Considering the interest in stimulating the browning process in metabolic disorders and the lack of clarity, evenness, and reproducibility of the preclinical models, the detailed description of an adipocyte differentiation protocol and the "de novo" development of a beige adipocyte phenotype has been described. Furthermore, the most described stimuli in inducing the browning process, such as PPAR-γ agonists (using rosiglitazone, RGZ) and β-adrenergic stimulators (using isoproterenol, ISO), were evaluated in order to describe their involvement in the browning process and identify a reference compound for the induction of the "de novo" browning. Methods Immortalized murine embryonic fibroblasts (3T3-L1) cells were differentiated for up to 17 days using a differentiation medium (DM) and a maintenance medium (MM) with or without RGZ or ISO to obtain both the mature white and the beige adipocyte phenotype. The differentiation was evaluated by the Oil Red O (ORO) staining assay, citrate synthase activity, and mitochondrial uncoupling protein 1 (UCP-1) immunodetection and expression performed on different days (T0, T3, T10, and T17) after the induction of differentiation. Results The results indicated that RGZ induced morphology and ORO-positive lipid deposits and increased the activity of citrate synthase enzyme and UCP-1 levels overlapping with a beige adipocyte phenotype after 17 days. ISO did not display a significant effect in these experimental conditions. Conclusion Overall, this work describes in depth the different phases of the adipocyte differentiation process by offering a detailed and reproducible "de novo" browning differentiation model. Furthermore, the efficacy of the stimulation of the PPAR-γ pathway in obtaining a beige adipocyte phenotype demonstrates that RGZ can induce the browning process and elects it as a perfect reference compound for experimental procedures in this field.
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Affiliation(s)
- Lorenzo Flori
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | | | - Giorgia Bray
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | - Chiara Ippolito
- Department of Clinical and Experimental Medicine, Unit of Histology and Medical Embryology, University of Pisa, Pisa, Italy
| | - Cristina Segnani
- Department of Clinical and Experimental Medicine, Unit of Histology and Medical Embryology, University of Pisa, Pisa, Italy
| | - Carolina Pellegrini
- Department of Clinical and Experimental Medicine, Unit of Histology and Medical Embryology, University of Pisa, Pisa, Italy
| | - Valentina Citi
- Department of Pharmacy, University of Pisa, Pisa, Italy
- Interdepartmental Research Centre of Ageing, Biology and Pathology, University of Pisa, Pisa, Italy
| | - Nunzia Bernardini
- Department of Clinical and Experimental Medicine, Unit of Histology and Medical Embryology, University of Pisa, Pisa, Italy
- Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, Pisa, Italy
| | - Alma Martelli
- Department of Pharmacy, University of Pisa, Pisa, Italy
- Interdepartmental Research Centre of Ageing, Biology and Pathology, University of Pisa, Pisa, Italy
- Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, Pisa, Italy
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, Pisa, Italy
- Interdepartmental Research Centre of Ageing, Biology and Pathology, University of Pisa, Pisa, Italy
- Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, Pisa, Italy
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Al Dow M, Secco B, Mouchiroud M, Rochette M, Gilio GR, Massicard M, Hardy M, Gélinas Y, Festuccia WT, Morissette MC, Manem VSK, Laplante M. Loss of VSTM2A promotes adipocyte hypertrophy and disrupts metabolic homeostasis. Obesity (Silver Spring) 2025; 33:522-536. [PMID: 39956640 PMCID: PMC11897849 DOI: 10.1002/oby.24224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/16/2024] [Accepted: 11/05/2024] [Indexed: 02/18/2025]
Abstract
OBJECTIVE Adipose tissue expands through hyperplasia and hypertrophy to store excess lipids, a process that is essential for the maintenance of metabolic homeostasis. The mechanisms regulating adipocyte recruitment from progenitors remain unclear. We have previously identified V-set and transmembrane domain-containing protein 2A (VSTM2A) as a factor promoting fat cell development in vitro. Whether VSTM2A impacts adipose tissue and systemic metabolism in vivo is still unknown. METHODS We generated VSTM2A knockout mice (Vstm2a-/-) using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) and fed them either a chow or high-fat diet. These mice were evaluated for body weight, adiposity, blood parameters, and glucose homeostasis. RESULTS Vstm2a-/- mice were viable and showed no body weight differences. Although adipose mass was similar, Vstm2a-/- mice had larger adipocytes, an effect linked to inflammation, ectopic lipid deposition, and impaired glucose and lipid metabolism. Transcriptomic analysis revealed that VSTM2A loss affects the expression of several genes in adipose tissue, including some related to the lysosome. Interestingly, acute lysosomal inhibition early in life is sufficient to cause adipocyte hypertrophy in adults. CONCLUSIONS VSTM2A is dispensable for adipose tissue formation, but its loss causes adipocyte hypertrophy and impairs glucose and lipid homeostasis. Our study also underscores a critical role of the lysosome in initiating adipogenesis.
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Affiliation(s)
- Manal Al Dow
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
| | - Blandine Secco
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
| | - Mathilde Mouchiroud
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
| | - Marianne Rochette
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
| | - Gustavo R. Gilio
- Institute of Biomedical Sciences, Department of Physiology and BiophysicsUniversity of São PauloSão PauloBrazil
| | - Mickael Massicard
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
| | - Marilou Hardy
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
| | - Yves Gélinas
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
| | - William T. Festuccia
- Institute of Biomedical Sciences, Department of Physiology and BiophysicsUniversity of São PauloSão PauloBrazil
| | - Mathieu C. Morissette
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
- Centre de recherche sur le cancer de l'Université LavalUniversité LavalQuebecQuébec CityCanada
- Département de Médecine, Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
| | - Venkata S. K. Manem
- Centre de recherche sur le cancer de l'Université LavalUniversité LavalQuebecQuébec CityCanada
- Département de Médecine, Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
- Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
| | - Mathieu Laplante
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
- Centre de recherche sur le cancer de l'Université LavalUniversité LavalQuebecQuébec CityCanada
- Département de Médecine, Faculté de MédecineUniversité LavalQuebecQuébec CityCanada
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Li H, Li J, Song C, Yang H, Luo Q, Chen M. Brown adipose tissue: a potential target for aging interventions and healthy longevity. Biogerontology 2024; 25:1011-1024. [PMID: 39377866 DOI: 10.1007/s10522-024-10137-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 08/30/2024] [Indexed: 10/09/2024]
Abstract
Brown Adipose Tissue (BAT) is a type of fat tissue that can generate heat and plays an important role in regulating body temperature and energy metabolism. Enhancing BAT activity through medication, exercise and other means has become a potential effective method for treating metabolic disorders. Recently, there has been increasing evidence suggesting a link between BAT and aging. As humans age, the volume and activity of BAT decrease, which may contribute to the development of age-related diseases. Multiple organelles signaling pathways have been reported to be involved in the aging process associated with BAT. Therefore, we aimed to review the evidence related to the association between aging process and BAT decreasing, analyze the potential of BAT as a predictive marker for age-related diseases, and explore potential therapeutic strategies targeting BAT for aging interventions and healthy longevity.
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Affiliation(s)
- Hongde Li
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China
- Department of Cardiology, West China Hospital, Sichuan University, #37 Guoxue Alley, Chengdu, 610041, PR China
| | - Junli Li
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Chengxiang Song
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China
- Department of Cardiology, West China Hospital, Sichuan University, #37 Guoxue Alley, Chengdu, 610041, PR China
| | - Haoran Yang
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China
- Department of Cardiology, West China Hospital, Sichuan University, #37 Guoxue Alley, Chengdu, 610041, PR China
| | - Qiang Luo
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
- Department of Cardiology, West China Hospital, Sichuan University, #37 Guoxue Alley, Chengdu, 610041, PR China.
| | - Mao Chen
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
- Department of Cardiology, West China Hospital, Sichuan University, #37 Guoxue Alley, Chengdu, 610041, PR China.
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Dakic T, Jeremic D, Lakic I, Jasnic N, Ruzicic A, Vujovic P, Jevdjovic T. Walnut supplementation increases levels of UCP1 and CD36 in brown adipose tissue independently of diet type. Mol Cell Biochem 2024; 479:1735-1745. [PMID: 38478220 DOI: 10.1007/s11010-024-04981-7] [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: 12/14/2023] [Accepted: 02/28/2024] [Indexed: 07/18/2024]
Abstract
Dietary interventions that modulate the brown adipose tissue (BAT) thermogenic activity could represent a promising therapy for metabolic disorders. In order to examine if dietary walnuts intake regulates the expression of BAT thermogenic markers levels in healthy and metabolically challenged (fructose fed) animals, rats were initially divided into the control and fructose-fed groups. After nine weeks, these groups were subdivided into the one kept on the original regimens and the other supplemented with walnuts. High-fructose diet resulted in an increased relative BAT mass and no change in UCP1 content, while the walnut supplementation increased the amount of UCP1 in BAT, but did not affect 5-HT, NA, DHPG content and DHPG/NA ratio regardless of the diet. Moreover, the CD36 levels were increased following the walnut consumption, unlike FATP1, GLUT1, GLUT4, and glycogen content which remained unchanged. Additionally, the BAT levels of activated IR and Akt were not affected by walnut consumption, while ERK signaling was decreased. Overall, we found that walnut consumption increased UCP1 and CD36 content in the BAT of both control and metabolically challenged rats, suggesting that FFAs represent the BAT preferred substrate under the previously described circumstances. This further implies that incorporating walnuts into the everyday diet may help to alleviate some symptoms of the metabolic disorder.
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Affiliation(s)
- Tamara Dakic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry "Ivan Djaja", Faculty of Biology, University of Belgrade, Belgrade, 11000, Serbia
| | - Dusan Jeremic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry "Ivan Djaja", Faculty of Biology, University of Belgrade, Belgrade, 11000, Serbia
| | - Iva Lakic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry "Ivan Djaja", Faculty of Biology, University of Belgrade, Belgrade, 11000, Serbia
| | - Nebojsa Jasnic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry "Ivan Djaja", Faculty of Biology, University of Belgrade, Belgrade, 11000, Serbia
| | - Aleksandra Ruzicic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry "Ivan Djaja", Faculty of Biology, University of Belgrade, Belgrade, 11000, Serbia
| | - Predrag Vujovic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry "Ivan Djaja", Faculty of Biology, University of Belgrade, Belgrade, 11000, Serbia
| | - Tanja Jevdjovic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry "Ivan Djaja", Faculty of Biology, University of Belgrade, Belgrade, 11000, Serbia.
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de Winne C, Pascual FL, Lopez-Vicchi F, Etcheverry-Boneo L, Mendez-Garcia LF, Ornstein AM, Lacau-Mengido IM, Sorianello E, Becu-Villalobos D. Neuroendocrine control of brown adipocyte function by prolactin and growth hormone. J Neuroendocrinol 2024; 36:e13248. [PMID: 36932836 DOI: 10.1111/jne.13248] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 02/08/2023] [Accepted: 02/11/2023] [Indexed: 03/06/2023]
Abstract
Growth hormone (GH) is fundamental for growth and glucose homeostasis, and prolactin for optimal pregnancy and lactation outcome, but additionally, both hormones have multiple functions that include a strong impact on energetic metabolism. In this respect, prolactin and GH receptors have been found in brown, and white adipocytes, as well as in hypothalamic centers regulating thermogenesis. This review describes the neuroendocrine control of the function and plasticity of brown and beige adipocytes, with a special focus on prolactin and GH actions. Most evidence points to a negative association between high prolactin levels and the thermogenic capacity of BAT, except in early development. During lactation and pregnancy, prolactin may be a contributing factor that limits unneeded thermogenesis, downregulating BAT UCP1. Furthermore, animal models of high serum prolactin have low BAT UCP1 levels and whitening of the tissue, while lack of Prlr induces beiging in WAT depots. These actions may involve hypothalamic nuclei, particularly the DMN, POA and ARN, brain centers that participate in thermogenesis. Studies on GH regulation of BAT function present some controversies. Most mouse models with GH excess or deficiency point to an inhibitory role of GH on BAT function. Even so, a stimulatory role of GH on WAT beiging has also been described, in accordance with whole-genome microarrays that demonstrate divergent response signatures of BAT and WAT genes to the loss of GH signaling. Understanding the physiology of BAT and WAT beiging may contribute to the ongoing efforts to curtail obesity.
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Affiliation(s)
- Catalina de Winne
- Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina
| | - Florencia L Pascual
- Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina
| | - Felicitas Lopez-Vicchi
- Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina
| | - Luz Etcheverry-Boneo
- Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina
| | - Luis F Mendez-Garcia
- Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina
| | - Ana Maria Ornstein
- Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina
| | - Isabel Maria Lacau-Mengido
- Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina
| | - Eleonora Sorianello
- Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina
| | - Damasia Becu-Villalobos
- Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina
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Flori L, Piragine E, Calderone V, Testai L. Role of hydrogen sulfide in the regulation of lipid metabolism: Implications on cardiovascular health. Life Sci 2024; 341:122491. [PMID: 38336275 DOI: 10.1016/j.lfs.2024.122491] [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: 01/29/2024] [Accepted: 02/05/2024] [Indexed: 02/12/2024]
Abstract
The World Health Organization (WHO) defines obesity as an urgency for health and a social emergency. Today around 39 % of people is overweight, of these over 13 % is obese. It is well-consolidated that the adipose cells are deputy to lipid storage under caloric excess; however, despite the classical idea that adipose tissue has exclusively a passive function, now it is known to be deeply involved in the regulation of systemic metabolism in physiological as well as under obesogenic conditions, with consequences on cardiovascular health. Beside two traditional types of adipose cells (white and brown), recently the beige one has been highlighted as the consequence of the healthy remodeling of white adipocytes, confirming their metabolic adaptability. In this direction, pharmacological, nutraceutical and nutrient-based approaches are addressed to positively influence inflammation and metabolism, thus contributing to reduce the obese-associated cardiovascular risk. In this scenario, hydrogen sulfide emerges as a new mediator that may regulate crucial targets involved in the regulation of metabolism. The current evidence demonstrates that hydrogen sulfide may induce peroxisome proliferator activated receptor γ (PPARγ), a crucial mediator of adipogenesis, inhibit the phosphorylation of perlipin-1 (plin-1), a protein implicated in the lipolysis, and finally promote browning process, through the release of irisin from skeletal muscle. The results summarized in this review suggest an important role of hydrogen sulfide in the regulation of metabolism and in the prevention/treatment of obese-associated cardiovascular diseases and propose new insight on the putative mechanisms underlying the release of hydrogen sulfide or its biosynthesis, delineating a further exciting field of application.
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Affiliation(s)
- Lorenzo Flori
- Department of Pharmacy, University of Pisa, via Bonanno, 6-56120 Pisa, Italy.
| | - Eugenia Piragine
- Department of Pharmacy, University of Pisa, via Bonanno, 6-56120 Pisa, Italy.
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, via Bonanno, 6-56120 Pisa, Italy.
| | - Lara Testai
- Department of Pharmacy, University of Pisa, via Bonanno, 6-56120 Pisa, Italy.
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Ma L, Xiong L, Huang G. Effects of mirabegron on brown adipose tissue and metabolism in humans: A systematic review and meta-analysis. Eur J Clin Pharmacol 2024; 80:317-333. [PMID: 38159219 DOI: 10.1007/s00228-023-03614-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/20/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Brown adipose tissue (BAT) has emerged as a potential therapeutic target for metabolic disorders due to its thermogenic and anti-obesity properties. β3-adrenergic receptor (β3-AR) agonists have also gained attention as potential agents for BAT activation and metabolic regulation. Mirabegron, a selective β3-AR-agonist used clinically for overactive bladder syndrome, has been explored for its utility in metabolic disorders. However, the controversy surrounding the ability of mirabegron to activate BAT to accelerate metabolism requires further investigation. The aim of this systematic review is to characterize comprehensively the impact of mirabegron on human BAT and its metabolism. METHODS We searched PubMed Central, Web of Science, Embase, and Cochrane Library databases for relevant papers published from the date of database inception to March 2023 for systematic reviews and meta-analyses. We extracted data on primary outcome indicators such as BAT volume, BAT activity, body temperature, and resting energy expenditure (REE), as well as secondary outcome indicators such as heart rate (HR), diastolic blood pressure (DBP), systolic blood pressure (SBP), non-esterified fatty acids (NEFA), blood glucose, and blood insulin from relevant studies. For studies that did not provide suitable data for meta-analysis, we used narrative data synthesis. For studies that provided suitable data for meta-analysis, we conducted meta-analysis using RevMan 5.4 software. RESULTS We reviewed 10 papers and included 6 in our meta-analysis. Our findings revealed no significant changes in BAT volume (p = 0.72) or blood glucose (p = 0.52) with mirabegron when compared to the placebo or pre-dose population. However, patients showed significant increases in BAT activity (p < 0.01), blood NEFA (p < 0.01), body temperature (p < 0.01), REE (p < 0.01), HR (p < 0.01), DBP (p < 0.01), SBP (p = 0.25), and blood insulin (p < 0.01). CONCLUSION Through our meta-analysis of 6 papers, we found that mirabegron has the potential to increase human BAT activity, REE, NEFA content, body temperature, HR, blood pressure, and blood insulin content. These effects may lead to reductions in blood glucose levels in obese/overweight and diabetic patients. Additionally, the activation of BAT by mirabegron could represent a novel approach for treating obesity, diabetes, and cardiovascular disease. TRIAL REGISTRATION NUMBER AND DATE CRD42023413446, 04/11/2023.
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Affiliation(s)
- Lili Ma
- First Clinical School of Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Lianqiu Xiong
- First Clinical School of Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Gang Huang
- Department of Radiology, Gansu Provincial Hospital, Lanzhou, China.
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10
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Li J, He J, He H, Wang X, Zhang S, He Y, Zhang J, Yuan C, Wang H, Xu D, Pan C, Yu H, Zou K. Sweet triterpenoid glycoside from Cyclocarya paliurus ameliorates obesity-induced insulin resistance through inhibiting the TLR4/NF-κB/NLRP3 inflammatory pathway. Curr Res Food Sci 2024; 8:100677. [PMID: 38303998 PMCID: PMC10831159 DOI: 10.1016/j.crfs.2024.100677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 11/19/2023] [Accepted: 01/08/2024] [Indexed: 02/03/2024] Open
Abstract
Our prophase studies have manifested that the sweet triterpenoid glycoside from the leaves of Cyclocarya paliurus (CPST) effectively improved the disorders of glucolipid metabolism in vitro and in patients. The current purpose was to further detect its mechanisms involved. The results demonstrated that CPST could ameliorate high-fat diet (HFD)-induced insulin resistance (IR), which was linked to reducing HFD-induced mice's body weight, serum glucose (GLUO), triglyceride (TG), total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C), lowering the area under the oral glucose tolerance curve and insulin tolerance, elevating the percentage of brown adipose, high-density lipoprotein cholesterol (HDL-C), reducing fat droplets of adipocytes in interscapular brown adipose tissue (iBAT) and cross-sectional area of adipocytes. Further studies manifested that CPST obviously downregulated TLR4, MyD88, NLRP3, ASC, caspase-1, cleased-caspase-1, IL-18, IL-1β, TXNIP, and GSDMD protein expressions and p-NF-кB/NF-кB ratio in iBAT. These aforementioned findings demonstrated that CPST ameliorated HFD induced IR by regulating TLR4/NF-κB/NLRP3 signaling pathway, which in turn enhancing insulin sensitivity and glucose metabolism.
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Affiliation(s)
- Jie Li
- Hubei Key Laboratory of Natural Products Research and Development & Yichang Key Laboratory of Development and Utilization of Health Products with Drug and Food Homology, China Three Gorges University, Yichang, Hubei, 443002, China
| | - Junyu He
- Basic Medical College of China Three Gorges University, Yichang, Hubei, 443002, China
| | - Haibo He
- Hubei Key Laboratory of Natural Products Research and Development & Yichang Key Laboratory of Development and Utilization of Health Products with Drug and Food Homology, China Three Gorges University, Yichang, Hubei, 443002, China
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, 442000, China
| | - Xiao Wang
- Hubei Key Laboratory of Natural Products Research and Development & Yichang Key Laboratory of Development and Utilization of Health Products with Drug and Food Homology, China Three Gorges University, Yichang, Hubei, 443002, China
| | - Shuran Zhang
- Hubei Key Laboratory of Natural Products Research and Development & Yichang Key Laboratory of Development and Utilization of Health Products with Drug and Food Homology, China Three Gorges University, Yichang, Hubei, 443002, China
| | - Yumin He
- Basic Medical College of China Three Gorges University, Yichang, Hubei, 443002, China
| | - Jihong Zhang
- Traditional Chinese Medicine Hospital of China Three Gorges University & Hubei Clinical Research Center for Functional Digestive Diseases of Traditional Chinese Medicine, Yichang, Hubei, 443001, China
| | - Chengfu Yuan
- Basic Medical College of China Three Gorges University, Yichang, Hubei, 443002, China
| | - HongWu Wang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, 430030, China
| | - Daoxiang Xu
- Seventh People's Hospital of Wenzhou, Wenzhou, Zhejiang, 325005, China
| | - Chaowang Pan
- Medical College of Ezhou Vocational University, Ezhou, Hubei, 436000, China
| | - Huifan Yu
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, 442000, China
| | - Kun Zou
- Hubei Key Laboratory of Natural Products Research and Development & Yichang Key Laboratory of Development and Utilization of Health Products with Drug and Food Homology, China Three Gorges University, Yichang, Hubei, 443002, China
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11
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Engin A. Endothelial Dysfunction in Obesity and Therapeutic Targets. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:489-538. [PMID: 39287863 DOI: 10.1007/978-3-031-63657-8_17] [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: 09/19/2024]
Abstract
Parallel to the increasing prevalence of obesity in the world, the mortality from cardiovascular disease has also increased. Low-grade chronic inflammation in obesity disrupts vascular homeostasis, and the dysregulation of adipocyte-derived endocrine and paracrine effects contributes to endothelial dysfunction. Besides the adipose tissue inflammation, decreased nitric oxide (NO)-bioavailability, insulin resistance (IR), and oxidized low-density lipoproteins (oxLDLs) are the main factors contributing to endothelial dysfunction in obesity and the development of cardiorenal metabolic syndrome. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in the profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Higher stiffness parameter β, increased oxidative stress, upregulation of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADP) oxidase in PVAT turn the macrophages into pro-atherogenic phenotypes by oxLDL-induced adipocyte-derived exosome-macrophage crosstalk and contribute to the endothelial dysfunction. In clinical practice, carotid ultrasound, higher leptin levels correlate with irisin over-secretion by human visceral and subcutaneous adipose tissues, and remnant cholesterol (RC) levels predict atherosclerotic disease in obesity. As a novel therapeutic strategy for cardiovascular protection, liraglutide improves vascular dysfunction by modulating a cyclic adenosine monophosphate (cAMP)-independent protein kinase A (PKA)-AMP-activated protein kinase (AMPK) pathway in PVAT in obese individuals. Because the renin-angiotensin-aldosterone system (RAAS) activity, hyperinsulinemia, and the resultant IR play key roles in the progression of cardiovascular disease in obesity, RAAS-targeted therapies contribute to improving endothelial dysfunction. By contrast, arginase reciprocally inhibits NO formation and promotes oxidative stress. Thus, targeting arginase activity as a key mediator in endothelial dysfunction has therapeutic potential in obesity-related vascular comorbidities. Obesity-related endothelial dysfunction plays a pivotal role in the progression of type 2 diabetes (T2D). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (thiazolidinedione), is a popular drug for treating diabetes; however, it leads to increased cardiovascular risk. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) significantly improves endothelial dysfunction and mortality occurring through redox-dependent mechanisms. Although endothelial dysfunction and oxidative stress are alleviated by either metformin or EMPA, currently used drugs to treat obesity-related diabetes neither possess the same anti-inflammatory potential nor simultaneously target endothelial cell dysfunction and obesity equally. While therapeutic interventions with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide or bariatric surgery reverse regenerative cell exhaustion, support vascular repair mechanisms, and improve cardiometabolic risk in individuals with T2D and obesity, the GLP-1 analog exendin-4 attenuates endothelial endoplasmic reticulum stress.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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12
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Carobbio S, Pellegrinelli V, Vidal-Puig A. Adipose Tissue Dysfunction Determines Lipotoxicity and Triggers the Metabolic Syndrome: Current Challenges and Clinical Perspectives. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:231-272. [PMID: 39287854 DOI: 10.1007/978-3-031-63657-8_8] [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: 09/19/2024]
Abstract
The adipose tissue organ is organised as distinct anatomical depots located all along the body axis, and it is constituted of three different types of adipocytes: white, beige and brown, which are integrated with vascular, immune, neural, and extracellular stroma cells. These distinct adipocytes serve different specialised functions. The main function of white adipocytes is to ensure healthy storage of excess nutrients/energy and its rapid mobilisation to supply the demand of energy imposed by physiological cues in other organs, whereas brown and beige adipocytes are designed for heat production through uncoupling lipid oxidation from energy production. The concerted action of the three types of adipocytes/tissues ensures an optimal metabolic status. However, when one or several of these adipose depots become dysfunctional because of sustained lipid/nutrient overload, then insulin resistance and associated metabolic complications ensue. These metabolic alterations close a vicious cycle that negatively affects the adipose tissue functionality and compromises global metabolic homeostasis. Optimising white adipose tissue expandability and ensuring its functional metabolic flexibility and/or promoting brown/beige mediated thermogenic activity are complementary strategies that counteract obesity and its associated lipotoxic metabolic effects. However, the development of these therapeutic approaches requires a deep understanding of adipose tissue in all broad aspects. In this chapter, we will discuss the characteristics of the different adipose tissue depots with respect to origins and precursors recruitment, plasticity, cellular composition, and expandability capacity potential as well as molecular and metabolic characteristic signatures in both physiological and pathophysiological conditions. Current antilipotoxic strategies for future clinical application are also discussed in this chapter.
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Affiliation(s)
- Stefania Carobbio
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
- Centro de Investigación Principe Felipe, Valencia, Spain.
| | - Vanessa Pellegrinelli
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Antonio Vidal-Puig
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
- Centro de Investigación Principe Felipe, Valencia, Spain.
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13
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Nucera S, Scarano F, Macrì R, Mollace R, Gliozzi M, Carresi C, Ruga S, Serra M, Tavernese A, Caminiti R, Coppoletta A, Cardamone A, Montalcini T, Pujia A, Palma E, Muscoli C, Barillà F, Musolino V, Mollace V. The Effect of an Innovative Combination of Bergamot Polyphenolic Fraction and Cynara cardunculus L. Extract on Weight Gain Reduction and Fat Browning in Obese Mice. Int J Mol Sci 2023; 25:191. [PMID: 38203362 PMCID: PMC10779365 DOI: 10.3390/ijms25010191] [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: 11/23/2023] [Revised: 12/16/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Obesity is one of the world's most serious public health issues, with a high risk of developing a wide range of diseases. As a result, focusing on adipose tissue dysfunction may help to prevent the metabolic disturbances commonly associated with obesity. Nutraceutical supplementation may be a crucial strategy for improving WAT inflammation and obesity and accelerating the browning process. The aim of this study was to perform a preclinical "proof of concept" study on Bergacyn®, an innovative formulation originating from a combination of bergamot polyphenolic fraction (BPF) and Cynara cardunculus (CyC), for the treatment of adipose tissue dysfunction. In particular, Bergacyn® supplementation in WD/SW-fed mice at doses of 50 mg/kg given orally for 12 weeks, was able to reduce body weight and total fat mass in the WD/SW mice, in association with an improvement in plasma biochemical parameters, including glycemia, total cholesterol, and LDL levels. In addition, a significant reduction in serum ALT levels was highlighted. The decreased WAT levels corresponded to an increased weight of BAT tissue, which was associated with a downregulation of PPARγ as compared to the vehicle group. Bergacyn® was able to restore PPARγ levels and prevent NF-kB overexpression in the WAT of mice fed a WD/SW diet, suggesting an improved oxidative metabolism and inflammatory status. These results were associated with a significant potentiation of the total antioxidant status in WD/SW mice. Finally, our data show, for the first time, that Bergacyn® supplementation may be a valuable approach to counteract adipose tissue dysfunction and obesity-associated effects on cardiometabolic risk.
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Affiliation(s)
- Saverio Nucera
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Federica Scarano
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Roberta Macrì
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Rocco Mollace
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Micaela Gliozzi
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Cristina Carresi
- Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (C.C.); (E.P.)
| | - Stefano Ruga
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Maria Serra
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Annamaria Tavernese
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Rosamaria Caminiti
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Annarita Coppoletta
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Antonio Cardamone
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Tiziana Montalcini
- Clinical Nutrition Unit, Department of Clinical and Experimental Medicine, University Magna of Græcia of Catanzaro, 88100 Catanzaro, Italy;
| | - Arturo Pujia
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy;
| | - Ernesto Palma
- Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (C.C.); (E.P.)
| | - Carolina Muscoli
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
| | - Francesco Barillà
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Vincenzo Musolino
- Pharmaceutical Biology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy;
| | - Vincenzo Mollace
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (S.N.); (F.S.); (R.M.); (M.G.); (S.R.); (M.S.); (A.T.); (R.C.); (A.C.); (A.C.); (C.M.)
- Renato Dulbecco Institute, Lamezia Terme, 88046 Catanzaro, Italy
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14
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Dąbrowska AM, Dudka J. Mirabegron, a Selective β3-Adrenergic Receptor Agonist, as a Potential Anti-Obesity Drug. J Clin Med 2023; 12:6897. [PMID: 37959362 PMCID: PMC10649615 DOI: 10.3390/jcm12216897] [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: 10/17/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
Obesity is becoming a global health epidemic. Brown and "beige" adipose tissue may produce heat, leading to energy expenditure enhancement and weight loss. Mirabegron, a selective β3-adrenergic receptor agonist, has been found to be effective as a brown adipose tissue activator, a "beige" cells stimulator and a metabolic homeostasis controller in animal and human studies. Although in animal studies, administration of mirabegron led to obesity improvement, significant weight loss in obese patients after mirabegron treatment has not been demonstrated so far, which may be associated with the too-short duration of the trials and the small number of participants in the studies. In humans, the most effective treatment for adipose tissue stimulation was high doses of mirabegron; however, cardiovascular side effects may limit the use of such doses, so the long-term safety must be evaluated. In cases of tachycardia or blood pressure elevation, the co-administration of a β1-adrenergic receptor blocker may be useful. It should be checked whether smaller doses of mirabegron, taken for a longer time, will be sufficient to stimulate brown and "beige" adipose tissue, leading to weight loss. The introduction of mirabegron into obesity treatment in the future will require long-term trials with larger numbers of subjects, to assess mirabegron efficacy, tolerability, and safety.
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Affiliation(s)
- Anna Maria Dąbrowska
- Department of Toxicology, Medical University of Lublin, Jaczewskiego Street 8b, 20-090 Lublin, Poland;
- Endocrinology Outpatient Clinic, Lublin, Poland
| | - Jarosław Dudka
- Department of Toxicology, Medical University of Lublin, Jaczewskiego Street 8b, 20-090 Lublin, Poland;
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15
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Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
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Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
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16
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Petito G, Cioffi F, Magnacca N, de Lange P, Senese R, Lanni A. Adipose Tissue Remodeling in Obesity: An Overview of the Actions of Thyroid Hormones and Their Derivatives. Pharmaceuticals (Basel) 2023; 16:ph16040572. [PMID: 37111329 PMCID: PMC10146771 DOI: 10.3390/ph16040572] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/04/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Metabolic syndrome and obesity have become important health issues of epidemic proportions and are often the cause of related pathologies such as type 2 diabetes (T2DM), hypertension, and cardiovascular disease. Adipose tissues (ATs) are dynamic tissues that play crucial physiological roles in maintaining health and homeostasis. An ample body of evidence indicates that in some pathophysiological conditions, the aberrant remodeling of adipose tissue may provoke dysregulation in the production of various adipocytokines and metabolites, thus leading to disorders in metabolic organs. Thyroid hormones (THs) and some of their derivatives, such as 3,5-diiodo-l-thyronine (T2), exert numerous functions in a variety of tissues, including adipose tissues. It is known that they can improve serum lipid profiles and reduce fat accumulation. The thyroid hormone acts on the brown and/or white adipose tissues to induce uncoupled respiration through the induction of the uncoupling protein 1 (UCP1) to generate heat. Multitudinous investigations suggest that 3,3',5-triiodothyronine (T3) induces the recruitment of brown adipocytes in white adipose depots, causing the activation of a process known as "browning". Moreover, in vivo studies on adipose tissues show that T2, in addition to activating brown adipose tissue (BAT) thermogenesis, may further promote the browning of white adipose tissue (WAT), and affect adipocyte morphology, tissue vascularization, and the adipose inflammatory state in rats receiving a high-fat diet (HFD). In this review, we summarize the mechanism by which THs and thyroid hormone derivatives mediate adipose tissue activity and remodeling, thus providing noteworthy perspectives on their efficacy as therapeutic agents to counteract such morbidities as obesity, hypercholesterolemia, hypertriglyceridemia, and insulin resistance.
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Affiliation(s)
- Giuseppe Petito
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", 81100 Caserta, Italy
| | - Federica Cioffi
- Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy
| | - Nunzia Magnacca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", 81100 Caserta, Italy
| | - Pieter de Lange
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", 81100 Caserta, Italy
| | - Rosalba Senese
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", 81100 Caserta, Italy
| | - Antonia Lanni
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", 81100 Caserta, Italy
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Taiwanese green propolis ameliorates metabolic syndrome via remodeling of white adipose tissue and modulation of gut microbiota in diet-induced obese mice. Biomed Pharmacother 2023; 160:114386. [PMID: 36773526 DOI: 10.1016/j.biopha.2023.114386] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/01/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
Excessive energy intake leads to dysbiosis of intestinal microbiota and puts surrounding tissues under oxidative stress and inflammation, contributing to the development of metabolic syndrome. Taiwanese green propolis (TGP) exhibits a broad spectrum of biological activities, including anti-bacterial, anti-inflammatory, and antioxidant properties. However, the benefits of TGP on metabolic syndrome have not been explained in detail. In this study, we examined the preventive effects of TGP on high-fat diet (HFD)-induced obesity. The results showed that TGP supplementation at 1000 ppm improved condition such as hyperlipidemia, fat accumulation, liver steatosis, and whitening of brown adipose tissue (BAT) in mice. In addition, we observed more cold-induced non-shivering thermogenesis by BAT in TGP treatment with 1000 ppm group. At lower dose of 500 ppm, TGP improved glucose intolerance and insulin insensitivity in HFD mice and restructured the composition of gut microbiota to reduce dysbiosis, which involved an increase in the abundance of metabolism-related bacteria such as Lachnospiraceae NK4A136 group and the decrease in Desulfovibrio. The change of dominant microbiota was associated with the homeostasis of blood glucose and lipid. Transcriptome and micro-western array analysis revealed that TGP supplementation at 500 ppm promoted the browning and adipogenesis in white adipose tissue (WAT), blocked inflammation signaling and attenuated reactive oxygen species, contributing to healthy WAT remodeling and offsetting negative metabolic effects of obesity. We concluded that TGP modulated the function of BAT, WAT, and gut microbiota, bringing a balance to the glucose and lipid homeostasis in the body.
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Colon-Mesa I, Sainz N, Corrales P, Collantes M, Kaldis P, Martinez JA, Medina-Gómez G, Moreno-Aliaga MJ, Escoté X. p27Kip1 Deficiency Impairs Brown Adipose Tissue Function Favouring Fat Accumulation in Mice. Int J Mol Sci 2023; 24:ijms24032664. [PMID: 36768986 PMCID: PMC9916555 DOI: 10.3390/ijms24032664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/13/2023] [Accepted: 01/22/2023] [Indexed: 02/01/2023] Open
Abstract
The aim of this work was to investigate the effect of the whole-body deletion of p27 on the activity of brown adipose tissue and the susceptibility to develop obesity and glucose homeostasis disturbances in mice, especially when subjected to a high fat diet. p27 knockout (p27-/-) and wild type (WT) mice were fed a normal chow diet or a high fat diet (HFD) for 10-weeks. Body weight and composition were assessed. Insulin and glucose tolerance tests and indirect calorimetry assays were performed. Histological analysis of interscapular BAT (iBAT) was carried out, and expression of key genes/proteins involved in BAT function were characterized by qPCR and Western blot. iBAT activity was estimated by 18F-fluorodeoxyglucose (18FDG) uptake with microPET. p27-/- mice were more prone to develop obesity and insulin resistance, exhibiting increased size of all fat depots. p27-/- mice displayed a higher respiratory exchange ratio. iBAT presented larger adipocytes in p27-/- HFD mice, accompanied by downregulation of both Glut1 and uncoupling protein 1 (UCP1) in parallel with defective insulin signalling. Moreover, p27-/- HFD mice exhibited impaired response to cold exposure, characterized by a reduced iBAT 18FDG uptake and difficulty to maintain body temperature when exposed to cold compared to WT HFD mice, suggesting reduced thermogenic capacity. These data suggest that p27 could play a role in BAT activation and in the susceptibility to develop obesity and insulin resistance.
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Affiliation(s)
- Ignacio Colon-Mesa
- Department of Nutrition, Food Science and Physiology and Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain
| | - Neira Sainz
- Department of Nutrition, Food Science and Physiology and Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain
| | - Patricia Corrales
- Department of Basic Sciences of Health, Area of Biochemistry and Molecular Biology, Universidad Rey Juan Carlos, Alcorcon, 28933 Madrid, Spain
| | - María Collantes
- Nuclear Medicine Department, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Philipp Kaldis
- Department of Clinical Sciences, Lund University, Clinical Research Centre (CRC), P.O. Box 50332, SE-202 13 Malmö, Sweden
- Lund University Diabetes Centre (LUDC), Lund University, SE-202 13 Malmö, Sweden
| | - José Alfredo Martinez
- Department of Nutrition, Food Science and Physiology and Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain
| | - Gema Medina-Gómez
- Department of Basic Sciences of Health, Area of Biochemistry and Molecular Biology, Universidad Rey Juan Carlos, Alcorcon, 28933 Madrid, Spain
- LAFEMEX Laboratory, Área de Bioquímica y Biología Molecular, Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcón, Spain
| | - María Jesús Moreno-Aliaga
- Department of Nutrition, Food Science and Physiology and Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain
- IdISNA—Navarra Institute for Health Research, 31008 Pamplona, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-948-425-600
| | - Xavier Escoté
- Department of Nutrition, Food Science and Physiology and Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain
- Eurecat, Centre Tecnològic de Catalunya, Unitat de Nutrició i Salut, 43204 Reus, Spain
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19
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Exercise training improves obesity-induced inflammatory signaling in rat brown adipose tissue. Biochem Biophys Rep 2022; 32:101398. [DOI: 10.1016/j.bbrep.2022.101398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 11/19/2022] [Accepted: 11/24/2022] [Indexed: 11/30/2022] Open
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20
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Hypoxia as a Double-Edged Sword to Combat Obesity and Comorbidities. Cells 2022; 11:cells11233735. [PMID: 36496995 PMCID: PMC9736735 DOI: 10.3390/cells11233735] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/14/2022] [Accepted: 11/17/2022] [Indexed: 11/24/2022] Open
Abstract
The global epidemic of obesity is tightly associated with numerous comorbidities, such as type II diabetes, cardiovascular diseases and the metabolic syndrome. Among the key features of obesity, some studies have suggested the abnormal expansion of adipose-tissue-induced local endogenous hypoxic, while other studies indicated endogenous hyperoxia as the opposite trend. Endogenous hypoxic aggravates dysfunction in adipose tissue and stimulates secretion of inflammatory molecules, which contribute to obesity. In contrast, hypoxic exposure combined with training effectively generate exogenous hypoxic to reduce body weight and downregulate metabolic risks. The (patho)physiological effects in adipose tissue are distinct from those of endogenous hypoxic. We critically assess the latest advances on the molecular mediators of endogenous hypoxic that regulate the dysfunction in adipose tissue. Subsequently we propose potential therapeutic targets in adipose tissues and the small molecules that may reverse the detrimental effect of local endogenous hypoxic. More importantly, we discuss alterations of metabolic pathways in adipose tissue and the metabolic benefits brought by hypoxic exercise. In terms of therapeutic intervention, numerous approaches have been developed to treat obesity, nevertheless durability and safety remain the major concern. Thus, a combination of the therapies that suppress endogenous hypoxic with exercise plans that augment exogenous hypoxic may accelerate the development of more effective and durable medications to treat obesity and comorbidities.
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21
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Min HY, Hwang J, Choi Y, Jo YH. Overexpressing the hydroxycarboxylic acid receptor 1 in mouse brown adipose tissue restores glucose tolerance and insulin sensitivity in diet-induced obese mice. Am J Physiol Endocrinol Metab 2022; 323:E231-E241. [PMID: 35830691 PMCID: PMC9423771 DOI: 10.1152/ajpendo.00084.2022] [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: 03/31/2022] [Revised: 07/05/2022] [Accepted: 07/09/2022] [Indexed: 11/22/2022]
Abstract
Interscapular brown adipose tissue (BAT) plays an important role in controlling glucose homeostasis. Increased glucose entry and glycolysis in BAT result in lactate production and release. The adipose tissue expresses the lactate receptor hydrocarboxylic acid receptor 1 (HCAR1), markedly downregulated in male diet-induced obese (DIO) and ob/ob mice. In this study, we examined the role of HCAR1 in BAT in controlling glucose homeostasis in male DIO mice. We overexpressed HCAR1 in BAT by injecting adeno-associated viruses (AAVs) expressing HCAR1 into the BAT pads of male DIO C57BL/6J mice. Overexpressing HCAR1 in BAT resulted in augmented glucose uptake by BAT in response to treatment with the HCAR1 agonist. HCAR1 overexpression elevated BAT temperature associated with increased thermogenic gene expression in BAT. HCAR1 overexpression prevented body weight gain in male DIO mice. Importantly, mice overexpressing HCAR1 in BAT exhibited improved glucose tolerance and insulin sensitivity. HCAR1 overexpression upregulated the Slc2a4 gene expression and promoted GLUT4 trafficking to the plasma membrane. In addition, mice overexpressing HCAR1 displayed a decrease in hormone-sensitive lipase (HSL) phosphorylation and increased lipogenic enzyme gene expression in BAT. Unlike DIO mice, overexpressing HCAR1 in BAT of mice fed a low-fat diet did not change body weight gain and glucose homeostasis. Taken together, our results support the interpretation that HCAR1 expressed in BAT promotes glucose entry and reduces lipolysis in BAT of male DIO mice. As activation of HCAR1 in BAT restores body weight, glucose tolerance, and insulin sensitivity in male DIO mice, our study suggests that interoceptive lactate detection via HCAR1 in BAT can regulate glucose and lipid substrate utilization and/or availability to promote healthy metabolism.NEW & NOTEWORTHY HCAR1 expressed in BAT can promote glucose entry and reduce lipolysis, resulting in body weight loss and increased insulin sensitivity. Hence, targeting HCAR1 in BAT would provide an alternative way to control body weight and euglycemia in individuals with obesity.
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Affiliation(s)
- Hyeon-Young Min
- The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York City, New York
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, New York City, New York
| | - Jiyeon Hwang
- The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York City, New York
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, New York City, New York
| | - Yuna Choi
- The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York City, New York
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, New York City, New York
| | - Young-Hwan Jo
- The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York City, New York
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, New York City, New York
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York City, New York
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22
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Ruiz-Malagón AJ, Rodríguez-Sojo MJ, Hidalgo-García L, Molina-Tijeras JA, García F, Pischel I, Romero M, Duarte J, Diez-Echave P, Rodríguez-Cabezas ME, Rodríguez-Nogales A, Gálvez J. The Antioxidant Activity of Thymus serpyllum Extract Protects against the Inflammatory State and Modulates Gut Dysbiosis in Diet-Induced Obesity in Mice. Antioxidants (Basel) 2022; 11:antiox11061073. [PMID: 35739969 PMCID: PMC9219752 DOI: 10.3390/antiox11061073] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/18/2022] [Accepted: 05/24/2022] [Indexed: 02/01/2023] Open
Abstract
Nowadays, there is an increasing interest in alternative therapies in the treatment of metabolic syndrome that combine efficacy and safety profiles. Therefore, this study aimed to evaluate the effect of an extract of Thymus serpyllum, containing rosmarinic acid, on high-fat diet (HFD)-induced obesity mice, highlighting the impact of its antioxidant activity on the inflammatory status and gut dysbiosis. The extract was administered daily (50, 100 and 150 mg/kg) in HFD-fed mice. The treatment reduced body weight gain, glucose and lipid metabolic profiles. Moreover, the extract ameliorated the inflammatory status, with the c-Jun N-terminal kinases (JUNK) pathway being involved, and showed a significant antioxidant effect by the reduction of radical scavenging activity and the mitigation of lipid peroxidation. Moreover, the extract was able to modulate the altered gut microbiota, restoring microbial richness and diversity, and augmenting the counts of short-chain fatty acid producing bacteria, which have been associated with the maintenance of gut permeability and weight regulation. In conclusion, the antioxidant activity of Thymus serpyllum extract displayed a positive impact on obesity and its metabolic alterations, also reducing systemic inflammation. These effects may be mediated by modulation of the gut microbiota.
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Affiliation(s)
- Antonio Jesús Ruiz-Malagón
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (A.J.R.-M.); (M.J.R.-S.); (L.H.-G.); (J.A.M.-T.); (M.R.); (J.D.); (A.R.-N.); (J.G.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
| | - María Jesús Rodríguez-Sojo
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (A.J.R.-M.); (M.J.R.-S.); (L.H.-G.); (J.A.M.-T.); (M.R.); (J.D.); (A.R.-N.); (J.G.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
| | - Laura Hidalgo-García
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (A.J.R.-M.); (M.J.R.-S.); (L.H.-G.); (J.A.M.-T.); (M.R.); (J.D.); (A.R.-N.); (J.G.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
| | - José Alberto Molina-Tijeras
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (A.J.R.-M.); (M.J.R.-S.); (L.H.-G.); (J.A.M.-T.); (M.R.); (J.D.); (A.R.-N.); (J.G.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
| | - Federico García
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
- Servicio Microbiología, Hospital Universitario Clínico San Cecilio, 18100 Granada, Spain
| | - Ivo Pischel
- Centre for Pharmacognosy and Phytotherapy, UCL School of Pharmacy, University of London, London WC1N 1AX, UK;
| | - Miguel Romero
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (A.J.R.-M.); (M.J.R.-S.); (L.H.-G.); (J.A.M.-T.); (M.R.); (J.D.); (A.R.-N.); (J.G.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto Salud Carlos III, 28029 Madrid, Spain
| | - Juan Duarte
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (A.J.R.-M.); (M.J.R.-S.); (L.H.-G.); (J.A.M.-T.); (M.R.); (J.D.); (A.R.-N.); (J.G.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto Salud Carlos III, 28029 Madrid, Spain
| | - Patricia Diez-Echave
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (A.J.R.-M.); (M.J.R.-S.); (L.H.-G.); (J.A.M.-T.); (M.R.); (J.D.); (A.R.-N.); (J.G.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
- Correspondence: (P.D.-E.); (M.E.R.-C.); Tel.: +34-958241519 (M.E.R.-C.)
| | - María Elena Rodríguez-Cabezas
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (A.J.R.-M.); (M.J.R.-S.); (L.H.-G.); (J.A.M.-T.); (M.R.); (J.D.); (A.R.-N.); (J.G.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
- Correspondence: (P.D.-E.); (M.E.R.-C.); Tel.: +34-958241519 (M.E.R.-C.)
| | - Alba Rodríguez-Nogales
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (A.J.R.-M.); (M.J.R.-S.); (L.H.-G.); (J.A.M.-T.); (M.R.); (J.D.); (A.R.-N.); (J.G.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
| | - Julio Gálvez
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (A.J.R.-M.); (M.J.R.-S.); (L.H.-G.); (J.A.M.-T.); (M.R.); (J.D.); (A.R.-N.); (J.G.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto Salud Carlos III, 28029 Madrid, Spain
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23
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Rahman MS, Jun H. The Adipose Tissue Macrophages Central to Adaptive Thermoregulation. Front Immunol 2022; 13:884126. [PMID: 35493493 PMCID: PMC9039244 DOI: 10.3389/fimmu.2022.884126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 03/22/2022] [Indexed: 11/13/2022] Open
Abstract
White fat stores excess energy, and thus its excessive expansion causes obesity. However, brown and beige fat, known as adaptive thermogenic fat, dissipates energy in the form of heat and offers a therapeutic potential to counteract obesity and metabolic disorders. The fat type-specific biological function is directed by its unique tissue microenvironment composed of immune cells, endothelial cells, pericytes and neuronal cells. Macrophages are major immune cells resident in adipose tissues and gained particular attention due to their accumulation in obesity as the primary source of inflammation. However, recent studies identified macrophages’ unique role and regulation in thermogenic adipose tissues to regulate energy expenditure and systemic energy homeostasis. This review presents the current understanding of macrophages in thermogenic fat niches with an emphasis on discrete macrophage subpopulations central to adaptive thermoregulation.
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Affiliation(s)
- Md Shamim Rahman
- Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX, United States
| | - Heejin Jun
- Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX, United States
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24
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Qin B, Qincao L, He S, Liao Y, Shi J, Xie F, Diao N, Bai L. Parathyroid hormone-related protein prevents high-fat-diet-induced obesity, hepatic steatosis and insulin resistance in mice. Endocr J 2022; 69:55-65. [PMID: 34408100 DOI: 10.1507/endocrj.ej20-0728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Obesity, closely related to systematic metabolic disorders, has become a major public health problem in recent decades. Here, we aimed to study the function of Parathyroid hormone-related protein (PTHrP) on high fat diet (HFD) induced murine obesity. Male C57BL/6J mice were transduced with adeno-associated virus vector encoding PTHrP (AAV-PTHrP) or adeno-associated virus control vector (AAV-Vehicle), following with HFD for 8 weeks. In addition, mice without transduction were fed on normal diet or HFD, respectively. Histological, metabolic and biochemical changes were detected. At the endpoint of experiment, body weight of mice treated with AAV-PTHrP did not increase as much as mice with AAV-Vehicle, but similar as mice with normal diet. Food efficiency ratio and weight of interscapular brown adipose tissue and epididymal white adipose tissue in mice overexpressed PTHrP were also lower than mice transducted with AAV-Vehicle. Besides, administration of AAV-PTHrP inhibited HFD-induced adipocyte hypertrophy. Protein level of PKA signaling pathway and thermogenic gene in adipose tissue exhibited a significant raise in HFD + AAV-PTHrP group, whereas transcription of inflammatory gene were decreased. Additionally, PTHrP overexpression ameliorated HFD-induced dyslipidemia, hepatic steatosis and insulin sensitivity. In HFD-induced murine obesity model, PTHrP is crucial to maintain metabolic homeostasis. PTHrP drives white adipose tissue browning and inhibits whitening of brown adipose tissue. Most importantly, PTHrP prevented HFD-induced obesity, hepatic steatosis and insulin resistance.
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Affiliation(s)
- Biyan Qin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Litao Qincao
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Shuying He
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Yan Liao
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Jie Shi
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Fang Xie
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Na Diao
- Guangdong Provincial Key Laboratory of Colorectal Diseases, Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Lan Bai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
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25
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Kidney Damage Caused by Obesity and Its Feasible Treatment Drugs. Int J Mol Sci 2022; 23:ijms23020747. [PMID: 35054932 PMCID: PMC8775419 DOI: 10.3390/ijms23020747] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/05/2022] [Accepted: 01/08/2022] [Indexed: 02/07/2023] Open
Abstract
The rapid growth of obesity worldwide has made it a major health problem, while the dramatic increase in the prevalence of obesity has had a significant impact on the magnitude of chronic kidney disease (CKD), especially in developing countries. A vast amount of researchers have reported a strong relationship between obesity and chronic kidney disease, and obesity can serve as an independent risk factor for kidney disease. The histological changes of kidneys in obesity-induced renal injury include glomerular or tubular hypertrophy, focal segmental glomerulosclerosis or bulbous sclerosis. Furthermore, inflammation, renal hemodynamic changes, insulin resistance and lipid metabolism disorders are all involved in the development and progression of obesity-induced nephropathy. However, there is no targeted treatment for obesity-related kidney disease. In this review, RAS inhibitors, SGLT2 inhibitors and melatonin would be presented to treat obesity-induced kidney injury. Furthermore, we concluded that melatonin can protect the kidney damage caused by obesity by inhibiting inflammation and oxidative stress, revealing its therapeutic potential.
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26
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Lopez-Vicchi F, De Winne C, Ornstein AM, Sorianello E, Toneatto J, Becu-Villalobos D. Severe Hyperprolactinemia Promotes Brown Adipose Tissue Whitening and Aggravates High Fat Diet Induced Metabolic Imbalance. Front Endocrinol (Lausanne) 2022; 13:883092. [PMID: 35757410 PMCID: PMC9226672 DOI: 10.3389/fendo.2022.883092] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/28/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The association of high serum prolactin and increased body weight is positive but controversial, therefore we hypothesized that additional factors such as diets and the impact of prolactin on brown adipose tissue may condition its metabolic effects. METHODS We used LacDrd2KO females with lifelong severe hyperprolactinemia due dopamine-D2 receptor deletion from lactotropes, and slow onset of metabolic disturbances, and compared them to their respective controls (Drd2 loxP/loxP ). Food intake, and binge eating was evaluated. We then challenged mice with a High Fat (HFD) or a Control Diet (CD) for 8 weeks, beginning at 3 months of age, when no differences in body weight are found between genotypes. At the end of the protocol brown and white adipose tissues were weighed, and thermogenic and lipogenic markers studied, using real time PCR (Ucp1, Cidea, Pgc1a, Lpl, adiponectin, Prlr) or immunohistochemistry (UCP1). Histochemical analysis of brown adipose tissue, and glucose tolerance tests were performed. RESULTS Hyperprolactinemic mice had increased food intake and binge eating behavior. Metabolic effects induced by a HFD were exacerbated in lacDrd2KO mice. Hyperprolactinemia aggravated HFD-induced body weight gain and glucose intolerance. In brown adipose tissue pronounced cellular whitening as well as decreased expression of the thermogenic markers Ucp1 and Pgc1a were observed in response to high prolactin levels, regardless of the diet, and furthermore, hyperprolactinemia potentiated the decrease in Cidea mRNA expression induced by HFD. In subcutaneous white adipose tissue hyperprolactinemia synergistically increased tissue weight, while decreasing Prlr, Adiponectin and Lpl mRNA levels regardless of the diet. CONCLUSIONS Pathological hyperprolactinemia has a strong impact in brown adipose tissue, lowering thermogenic markers and evoking tissue whitening. Furthermore, it modifies lipogenic markers in subcutaneous white adipose, and aggravates HFD-induced glucose intolerance and Cidea decrease. Therefore, severe high prolactin levels may target BAT function, and furthermore represent an adjuvant player in the development of obesity induced by high fat diets.
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27
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Tournissac M, Leclerc M, Valentin-Escalera J, Vandal M, Bosoi CR, Planel E, Calon F. Metabolic determinants of Alzheimer's disease: A focus on thermoregulation. Ageing Res Rev 2021; 72:101462. [PMID: 34534683 DOI: 10.1016/j.arr.2021.101462] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/09/2021] [Accepted: 09/11/2021] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is a complex age-related neurodegenerative disease, associated with central and peripheral metabolic anomalies, such as impaired glucose utilization and insulin resistance. These observations led to a considerable interest not only in lifestyle-related interventions, but also in repurposing insulin and other anti-diabetic drugs to prevent or treat dementia. Body temperature is the oldest known metabolic readout and mechanisms underlying its maintenance fail in the elderly, when the incidence of AD rises. This raises the possibility that an age-associated thermoregulatory deficit contributes to energy failure underlying AD pathogenesis. Brown adipose tissue (BAT) plays a central role in thermogenesis and maintenance of body temperature. In recent years, the modulation of BAT activity has been increasingly demonstrated to regulate energy expenditure, insulin sensitivity and glucose utilization, which could also provide benefits for AD. Here, we review the evidence linking thermoregulation, BAT and insulin-related metabolic defects with AD, and we propose mechanisms through which correcting thermoregulatory impairments could slow the progression and delay the onset of AD.
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Peres Valgas da Silva C, Calmasini F, Alexandre EC, Raposo HF, Delbin MA, Monica FZ, Zanesco A. The effects of mirabegron on obesity-induced inflammation and insulin resistance are associated with brown adipose tissue activation but not beiging in the subcutaneous white adipose tissue. Clin Exp Pharmacol Physiol 2021; 48:1477-1487. [PMID: 34343353 DOI: 10.1111/1440-1681.13566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 07/28/2021] [Accepted: 07/30/2021] [Indexed: 01/22/2023]
Abstract
Mirabegron is a selective β₃-adrenergic receptors agonist, which has been recently shown to improve metabolic health in rodents and humans. In this study, we investigated the effects of 2-week mirabegron treatment on the metabolic parameters of mice with a diet-induced obesity (DIO). C57BL/6JUnib mice were divided into control (CTR) and obese (OB) groups treated with vehicle, and an OB group treated with mirabegron (OB + MIRA). The obese groups were fed a high-fat diet for 12 weeks. Mirabegron (10 mg/kg/day) was administrated orally by gavage from weeks 10-12. After 2 weeks of mirabegron treatment, the energy expenditure was assessed with indirect calorimetry. Blood glucose, insulin, glycerol, free fatty acids (FFA), thiobarbituric acid reactive substance (TBAR), and tumour necrosis factor (TNF)-α levels were also assessed, and the HOMA index was determined. Liver tissue, brown adipose tissue (BAT), and inguinal white adipose tissue (iWAT) samples were collected for histological examination. The protein expressions of uncoupling protein 1 (UCP1) and mitochondrial transcription factor A (TFAM) were assessed using western blotting of the BAT and iWAT samples. In this study, mirabegron increased the energy expenditure and decreased adiposity in OB + MIRA. Increased UCP1 expression in BAT without changes in iWAT was also found. Mirabegron decreased circulating levels of FFA, glycerol, insulin, TNF-α, TBARS and HOMA index. DIO significantly increased the lipid deposits in the liver and BAT, but mirabegron partially reversed this change. Our findings indicate that treatment with mirabegron decreased inflammation and improved metabolism in obese mice. This effect was associated with increased BAT-mediated energy expenditure, but not iWAT beiging, which suggests that mirabegron might be useful for the treatment of obesity and diabetes.
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Affiliation(s)
- Carmem Peres Valgas da Silva
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Physical Education, Institute of Biosciences, São Paulo State University (UNESP), Rio Claro, Brazil
| | - Fabiano Calmasini
- Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Eduardo Costa Alexandre
- Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Helena Fonseca Raposo
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Maria Andreia Delbin
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Fabiola Zakia Monica
- Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Angelina Zanesco
- Department of Physical Education, Institute of Biosciences, São Paulo State University (UNESP), Rio Claro, Brazil
- Medical School, Graduate Program in Environmental Health, Metropolitan University of Santos, Santos, Brazil
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George J, Zhang Y, Sloan J, Sims JM, Imig JD, Zhao X. Tim-1 Deficiency Aggravates High-Fat Diet-Induced Steatohepatitis in Mice. Front Immunol 2021; 12:747794. [PMID: 34675931 PMCID: PMC8523998 DOI: 10.3389/fimmu.2021.747794] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/16/2021] [Indexed: 11/08/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is commonly associated with obesity and characterized by excessive lipid accumulation and liver inflammation. The T cell immunoglobulin and mucin domain 1 (Tim-1), also known as hepatitis A virus cellular receptor 1 (Havcr-1) and kidney injury molecule 1 (Kim-1), has been shown to affect innate immunity-driven proinflammatory cascade in liver ischemia-reperfusion injury. However, its contribution to obesity-related NAFLD/NASH remains unknown. Thus, this study was designed to evaluate the role of Tim-1 in obesity-related liver inflammation and injury in wild-type (WT) and Tim-1-deficient (Tim-1-/-) C57BL/6J mice fed a high-fat diet (HFD) for 5-6 months. HFD feeding induced steatosis and upregulated Tim-1 gene expression in the liver of WT mice. Surprisingly, Tim-1-/- mice on HFD diet exhibited an exacerbation of hepatic steatosis, accompanied with an elevation of protein levels of fatty acid translocase CD36 and sterol regulatory element binding protein 1 (SREBP1). Tim-1 deficiency also enhanced HFD-induced liver inflammation and injury, as evidenced by augmented increase in hepatic expression of pro-inflammatory factor lipocalin 2 and elevated serum alanine transaminase (ALT). In addition, gene expression of type I, III and IV collagens and liver fibrosis were greatly enhanced in HFD Tim-1-/- mice compared with HFD WT mice. HFD-induced hepatic expression of YM-1, a specific mouse M2 macrophage marker, was further upregulated by deletion of Tim-1. Together, these results show that Tim-1 deficiency aggravates the effects of HFD diet on lipid accumulation and liver fibrosis, most likely through enhanced infiltration and activation of inflammatory cells.
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Affiliation(s)
- Jasmine George
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Yuanyuan Zhang
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Jacob Sloan
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Joya M Sims
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - John D Imig
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Xueying Zhao
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
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Role of RAGE in obesity-induced adipose tissue inflammation and insulin resistance. Cell Death Discov 2021; 7:305. [PMID: 34686659 PMCID: PMC8536716 DOI: 10.1038/s41420-021-00711-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/22/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022] Open
Abstract
Obesity is known to be associated with adipose tissue inflammation and insulin resistance. Importantly, in obesity, the accumulation of proinflammatory macrophages in adipose tissue correlates with insulin resistance. We hypothesized that the receptor for advanced glycation end products (RAGE) and associated ligands are involved in adipose tissue insulin resistance, and that the activation of the AGE–RAGE axis plays an important role in obesity-associated inflammation. C57BL/6J mice (WT) and RAGE deficient (RAGE−/−) mice were fed a high fat diet (HFD) and subjected to glucose and insulin tolerance tests. Epdidymal adipose tissue (eAT) was collected and adipose stromal vascular cells isolated using flow cytometry. Visceral adipose tissue macrophage polarization was assessed by quantitative real time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues. In additional studies, cell trafficking was assessed by injecting labeled blood monocytes into recipient mice. RAGE−/− mice displayed improved insulin sensitivity and glucose tolerance, accompanied by decreased body weight and eAT mass. Exogenous methylglyoxal (MGO) impaired insulin-stimulated AKT signaling in adipose tissues from WT mice fed a normal chow diet, but not in RAGE−/− mice. In contrast, in obese mice, treatment with MGO did not reduce insulin-induced phosphorylation of AKT in WT-HFD mice. Moreover, insulin-induced AKT phosphorylation was found to be impaired in adipose tissue from RAGE−/−-HFD mice. RAGE−/− mice displayed improved inflammatory profiles and evidence for increased adipose tissue browning. This observation is consistent with the finding of reduced plasma levels of FFA, glycerol, IL-6, and leptin in RAGE−/− mice compared to WT mice. Collectively the data demonstrate that RAGE-mediated adipose tissue inflammation and insulin-signaling are potentially important mechanisms that contribute to the development of obesity-associated insulin resistance.
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Antiobesity and Antidiabetic Effects of Portulaca oleracea Powder Intake in High-Fat Diet-Induced Obese C57BL/6 Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5587848. [PMID: 34257685 PMCID: PMC8257357 DOI: 10.1155/2021/5587848] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/30/2021] [Indexed: 11/17/2022]
Abstract
This study investigated the hypothesis that Portulaca oleracea L. exerts antiobesity and antidiabetic effects by evaluating blood lipid profiles, blood glucose control factors, protein expression of lipid metabolism, and insulin sensitivity improvement. Three groups of high-fat diet (HFD) induced obese C57BL/6 mice (n = 8) received treatment with low (5%; HFD + PO5%) or high (10%; HFD + PO10%) concentrations of P. oleracea powder for 12 weeks or no treatment (HFD) and were compared with each other and a fourth control group. Weight gain was reduced by 34% in the HFD + PO10% group compared to the HFD group. Moreover, the perirenal and epididymal fat contents in the HFD + PO10% group were 6.3-fold and 1.5-fold, respectively, lower than those in the HFD group. The atherogenic index (AI) and cardiac risk factor (CRF) results in the P. oleracea-treated groups were significantly lower than those in the HFD group. The homeostasis model assessment of insulin resistance (HOMA-IR) levels was lower in the HFD + PO10% group than in the HFD group. The protein expression levels of the proliferator-activated receptor (PPAR)-α, glucose transporter (GLUT) 4 and PPAR-γ were upregulated in the HFD + PO10% group compared to the HFD group. However, the protein expression levels of tumor necrosis factor (TNF)-α were lower in the P. oleracea-treated groups than in the HFD group. Our results demonstrate that P. oleracea powder could be effectively used to treat and prevent obesity and diabetes-associated diseases through suppression of weight gain and reduction in body fat and blood glucose levels.
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Inflammation in Metabolic and Cardiovascular Disorders-Role of Oxidative Stress. Life (Basel) 2021; 11:life11070672. [PMID: 34357044 PMCID: PMC8308054 DOI: 10.3390/life11070672] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases (CVD) constitute the main cause of death worldwide. Both inflammation and oxidative stress have been reported to be involved in the progress of CVD. It is well known that generation of oxidative stress during the course of CVD is involved in tissue damage and inflammation, causing deleterious effects such as hypertension, dysfunctional metabolism, endothelial dysfunction, stroke, and myocardial infarction. Remarkably, natural antioxidant strategies have been increasingly discovered and are subject to current scientific investigations. Here, we addressed the activation of immune cells in the context of ROS production, as well as how their interaction with other cellular players and further (immune) mediators contribute to metabolic and cardiovascular disorders. We also highlight how a dysregulated complement system contributes to immune imbalance and tissue damage in the context of increases oxidative stress. Additionally, modulation of hypothalamic oxidative stress is discussed, which may offer novel treatment strategies for type-2 diabetes and obesity. Together, we provide new perspectives on therapy strategies for CVD caused by oxidative stress, with a focus on oxidative stress.
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Cohen P, Kajimura S. The cellular and functional complexity of thermogenic fat. Nat Rev Mol Cell Biol 2021; 22:393-409. [PMID: 33758402 PMCID: PMC8159882 DOI: 10.1038/s41580-021-00350-0] [Citation(s) in RCA: 291] [Impact Index Per Article: 72.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2021] [Indexed: 02/01/2023]
Abstract
Brown and beige adipocytes are mitochondria-enriched cells capable of dissipating energy in the form of heat. These thermogenic fat cells were originally considered to function solely in heat generation through the action of the mitochondrial protein uncoupling protein 1 (UCP1). In recent years, significant advances have been made in our understanding of the ontogeny, bioenergetics and physiological functions of thermogenic fat. Distinct subtypes of thermogenic adipocytes have been identified with unique developmental origins, which have been increasingly dissected in cellular and molecular detail. Moreover, several UCP1-independent thermogenic mechanisms have been described, expanding the role of these cells in energy homeostasis. Recent studies have also delineated roles for these cells beyond the regulation of thermogenesis, including as dynamic secretory cells and as a metabolic sink. This Review presents our current understanding of thermogenic adipocytes with an emphasis on their development, biological functions and roles in systemic physiology.
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Affiliation(s)
- Paul Cohen
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA.
| | - Shingo Kajimura
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
- Department of Cell and Tissue Biology, UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
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34
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Pang H, Ling D, Cheng Y, Akbar R, Jin L, Ren J, Wu H, Chen B, Zhou Y, Zhu H, Zhou Y, Huang H, Sheng J. Gestational high-fat diet impaired demethylation of Pparα and induced obesity of offspring. J Cell Mol Med 2021; 25:5404-5416. [PMID: 33955677 PMCID: PMC8184666 DOI: 10.1111/jcmm.16551] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 03/06/2021] [Accepted: 03/30/2021] [Indexed: 01/12/2023] Open
Abstract
Gestational and postpartum high‐fat diets (HFDs) have been implicated as causes of obesity in offspring in later life. The present study aimed to investigate the effects of gestational and/or postpartum HFD on obesity in offspring. We established a mouse model of HFD exposure that included gestation, lactation and post‐weaning periods. We found that gestation was the most sensitive period, as the administration of a HFD impaired lipid metabolism, especially fatty acid oxidation in both foetal and adult mice, and caused obesity in offspring. Mechanistically, the DNA hypermethylation level of the nuclear receptor, peroxisome proliferator‐activated receptor‐α (Pparα), and the decreased mRNA levels of ten‐eleven translocation 1 (Tet1) and/or ten‐eleven translocation 2 (Tet2) were detected in the livers of foetal and adult offspring from mothers given a HFD during gestation, which was also associated with low Pparα expression in hepatic cells. We speculated that the hypermethylation of Pparα resulted from the decreased Tet1/2 expression in mothers given a HFD during gestation, thereby causing lipid metabolism disorders and obesity. In conclusion, this study demonstrates that a HFD during gestation exerts long‐term effects on the health of offspring via the DNA demethylation of Pparα, thereby highlighting the importance of the gestational period in regulating epigenetic mechanisms involved in metabolism.
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Affiliation(s)
- Haiyan Pang
- Department of Reproductive Medicine, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,The Key Laboratory of Reproductive Genetics （Zhejiang University School of Medicine), Ministry of Education, Hangzhou, China
| | - Dandan Ling
- Department of Reproductive Medicine, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,The Key Laboratory of Reproductive Genetics （Zhejiang University School of Medicine), Ministry of Education, Hangzhou, China
| | - Yi Cheng
- Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China
| | - Rubab Akbar
- Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, China
| | - Luyang Jin
- Department of Reproductive Medicine, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,The Key Laboratory of Reproductive Genetics （Zhejiang University School of Medicine), Ministry of Education, Hangzhou, China
| | - Jun Ren
- Department of Reproductive Medicine, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Haiyan Wu
- Department of Reproductive Medicine, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,The Key Laboratory of Reproductive Genetics （Zhejiang University School of Medicine), Ministry of Education, Hangzhou, China
| | - Bin Chen
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yin Zhou
- Center for Reproductive Medicine, School of Medicine, the Second Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Hong Zhu
- Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China
| | - Yuzhong Zhou
- The Key Laboratory of Reproductive Genetics （Zhejiang University School of Medicine), Ministry of Education, Hangzhou, China
| | - Hefeng Huang
- The Key Laboratory of Reproductive Genetics （Zhejiang University School of Medicine), Ministry of Education, Hangzhou, China.,Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China
| | - Jianzhong Sheng
- The Key Laboratory of Reproductive Genetics （Zhejiang University School of Medicine), Ministry of Education, Hangzhou, China.,Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, China
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van Beek SMM, Kalinovich A, Schaart G, Bengtsson T, Hoeks J. Prolonged β 2-adrenergic agonist treatment improves glucose homeostasis in diet-induced obese UCP1 -/- mice. Am J Physiol Endocrinol Metab 2021; 320:E619-E628. [PMID: 33522400 DOI: 10.1152/ajpendo.00324.2020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Prolonged supplementation with the β2-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via β2-adrenoceptor (β2-AR)-mediated effects in the skeletal muscle and liver. However, since rodents have, in contrast to-especially diabetic-humans, substantial quantities of brown adipose tissue (BAT) and clenbuterol has affinity to β1- and β3-ARs, the contribution of BAT to these improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncoupling protein 1-deficient (UCP1-/-) mice, lacking thermogenic BAT, versus wild-type (WT) mice. Anesthetized WT and UCP1-/- C57Bl/6 mice were injected with saline or clenbuterol and whole body oxygen consumption was measured. Furthermore, male WT and UCP1-/- C57Bl/6 mice were subjected to 17-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment between weeks 13 and 17. Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in week 15 and 17, respectively. Clenbuterol increased oxygen consumption approximately twofold in WT mice. This increase was blunted in UCP1-/- mice, indicating clenbuterol-mediated activation of BAT thermogenesis. High-fat feeding induced diabetogenic phenotypes in both genotypes. However, low-dose clenbuterol treatment for 2 wk significantly reduced fasting blood glucose by 12.9% in WT and 14.8% in UCP1-/- mice. Clenbuterol treatment improved glucose and insulin tolerance in both genotypes compared with HFD controls and normalized to chow-fed control mice independent of body mass and composition alterations. Clenbuterol improved whole body glucose homeostasis independent of UCP1. Given the low human abundancy of BAT, β2-AR agonist treatment provides a potential novel route for glucose disposal in diabetic humans.NEW & NOTEWORTHY Improvements in whole body glucose homeostasis of rodents upon prolonged β2-adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the β2-AR agonist clenbuterol induces BAT activation in mice. However, we also demonstrate that prolonged clenbuterol supplementation robustly improves whole body glucose and insulin tolerance in a similar way in both DIO WT and UCP1-/- mice, indicating that β2-AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis.
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Affiliation(s)
- Sten M M van Beek
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Anastasia Kalinovich
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Gert Schaart
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Tore Bengtsson
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Joris Hoeks
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
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Boulet N, Luijten IHN, Cannon B, Nedergaard J. Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition. Am J Physiol Endocrinol Metab 2021; 320:E359-E378. [PMID: 33284094 PMCID: PMC8260372 DOI: 10.1152/ajpendo.00352.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Cold- and diet-induced recruitment of brown adipose tissue (BAT) and the browning of white adipose tissue (WAT) are dynamic processes, and the recruited state attained is a state of dynamic equilibrium, demanding continuous stimulation to be maintained. An involvement of macrophages, classical proinflammatory (M1) or alternatively activated anti-inflammatory (M2), is presently discussed as being an integral part of these processes. If these macrophages play a mediatory role in the recruitment process, such an involvement would have to be maintained in the recruited state. We have, therefore, investigated whether the recruited state of these tissues is associated with macrophage accretion or attrition. We found no correlation (positive or negative) between total UCP1 mRNA levels (as a measure of recruitment) and proinflammatory macrophages in any adipose depot. We found that in young chow-fed mice, cold-induced recruitment correlated with accretion of anti-inflammatory macrophages; however, such a correlation was not seen when cold-induced recruitment was studied in diet-induced obese mice. Furthermore, the anti-inflammatory macrophage accretion was mediated via β1/β2-adrenergic receptors; yet, in their absence, and thus in the absence of macrophage accretion, recruitment proceeded normally. We thus conclude that the classical recruited state in BAT and inguinal (brite/beige) WAT is not paralleled by macrophage accretion or attrition. Our results make mediatory roles for macrophages in the recruitment process less likely.NEW & NOTEWORTHY A regulatory or mediatory role-positive or negative-for macrophages in the recruitment of brown adipose tissue is presently discussed. As the recruited state in the tissue is a dynamic process, maintenance of the recruited state would need persistent alterations in macrophage complement. Contrary to this expectation, we demonstrate here an absence of alterations in macrophage complement in thermogenically recruited brown-or brite/beige-adipose tissues. Macrophage regulation of thermogenic capacity is thus less likely.
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MESH Headings
- Adipose Tissue, Beige/cytology
- Adipose Tissue, Beige/physiology
- Adipose Tissue, Brown/cytology
- Adipose Tissue, Brown/physiology
- Animals
- Diet/adverse effects
- Gene Expression Regulation
- Macrophages/cytology
- Macrophages/physiology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Obesity/etiology
- Obesity/metabolism
- Obesity/pathology
- Receptors, Adrenergic, beta-1/physiology
- Receptors, Adrenergic, beta-2/physiology
- Thermogenesis
- Uncoupling Protein 1/genetics
- Uncoupling Protein 1/metabolism
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Affiliation(s)
- Nathalie Boulet
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Ineke H N Luijten
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Barbara Cannon
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Jan Nedergaard
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
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37
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Wei (魏彤) T, Gao (高晶) J, Huang (黄程淋) C, Song (宋蓓) B, Sun (孙孟炜) M, Shen (沈伟利) W. SIRT3 (Sirtuin-3) Prevents Ang II (Angiotensin II)-Induced Macrophage Metabolic Switch Improving Perivascular Adipose Tissue Function. Arterioscler Thromb Vasc Biol 2021; 41:714-730. [PMID: 33327751 DOI: 10.1161/atvbaha.120.315337] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Infiltrated macrophages actively promote perivascular adipose tissue remodeling and represent a dominant population in the perivascular adipose tissue microenvironment of hypertensive mice. However, the role of macrophages in initiating metabolic inflammation remains uncertain. SIRT3 (sirtuin-3), a NAD-dependent deacetylase, is sensitive to metabolic status and mediates adaptation responses. In this study, we investigated the role of SIRT3-mediated metabolic shift in regulating NLRP3 (Nod-like receptor family pyrin domain-containing 3) inflammasome activation. Approach and Results: Here, we report that Ang II (angiotensin II) accelerates perivascular adipose tissue inflammation and fibrosis, accompanied by NLRP3 inflammasome activation and IL (interleukin)-1β secretion in myeloid SIRT3 knockout (SIRT3-/-) mice. This effect is associated with adipose tissue mitochondrial dysfunction. In vitro studies indicate that the deletion of SIRT3 in bone marrow-derived macrophages induces IL-1β production by shifting the metabolic phenotype from oxidative phosphorylation to glycolysis. Mechanistically, SIRT3 deacetylates and activates PDHA1 (pyruvate dehydrogenase E1 alpha) at lysine 83, and the loss of SIRT3 leads to PDH activity decrease and lactate accumulation. Knocking down LDHA (lactate dehydrogenase A) or using carnosine, a buffer against lactic acid, attenuates IL-1β secretion. Furthermore, the blockade of IL-1β from macrophages into brown adipocytes restores thermogenic markers and mitochondrial oxygen consumption. Moreover, NLRP3 knockout (NLRP3-/-) mice exhibited reduced IL-1β production while rescuing the mitochondrial function of brown adipocytes and alleviating perivascular adipose tissue fibrosis. CONCLUSIONS SIRT3 represents a potential therapeutic target to attenuate NLRP3-related inflammation. Pharmacological targeting of glycolytic metabolism may represent an effective therapeutic approach.
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Affiliation(s)
- Tong Wei (魏彤)
- Department of Cardiovascular Medicine, Department of Hypertension, and Department of General Practice, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China (T.W., J.G., C.H., B.S., W.S.)
| | - Jing Gao (高晶)
- Department of Cardiovascular Medicine, Department of Hypertension, and Department of General Practice, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China (T.W., J.G., C.H., B.S., W.S.)
| | - Chenglin Huang (黄程淋)
- Department of Cardiovascular Medicine, Department of Hypertension, and Department of General Practice, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China (T.W., J.G., C.H., B.S., W.S.)
| | - Bei Song (宋蓓)
- Department of Cardiovascular Medicine, Department of Hypertension, and Department of General Practice, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China (T.W., J.G., C.H., B.S., W.S.)
| | - Mengwei Sun (孙孟炜)
- Department of Cardiovascular Medicine, Department of Hypertension, and Department of General Practice, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China (T.W., J.G., C.H., B.S., W.S.)
| | - Weili Shen (沈伟利)
- Key Laboratory of State General Administration of Sport, Shanghai Research Institute of Sports
Science, China (M.S.)
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Zhang S, Sousa A, Lin M, Iwano A, Jain R, Ma B, Lee CM, Park JW, Kamle S, Carlson R, Lee GG, Elias JA, Wands JR. Role of Chitinase 3-Like 1 Protein in the Pathogenesis of Hepatic Insulin Resistance in Nonalcoholic Fatty Liver Disease. Cells 2021; 10:201. [PMID: 33498326 PMCID: PMC7909438 DOI: 10.3390/cells10020201] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/15/2021] [Accepted: 01/17/2021] [Indexed: 02/08/2023] Open
Abstract
A recently discovered human glycoprotein, chitinase 3-like 1 (Chi3L1), may play a role in inflammation, tissue remodeling, and visceral fat accumulation. We hypothesize that Chi3L1 gene expression is important in the development of hepatic insulin resistance characterized by the generation of pAKT, pGSK, and pERK in wild type and Chi3L1 knockout (KO) murine liver following insulin stimulation. The Chi3L1 gene and protein expression was evaluated by Real Time PCR and ELISA; lipid accumulation in hepatocytes was also assessed. To alter Chi3L1 function, three different anti-Chi3L1 monoclonal antibodies (mAbs) were administered in vivo and effects on the insulin signaling cascade and hepatic lipid deposition were determined. Transmission of the hepatic insulin signal was substantially improved following KO of the CHi3L1 gene and there was reduced lipid deposition produced by a HFD. The HFD-fed mice exhibited increased Chi3L1 expression in the liver and there was impaired insulin signal transduction. All three anti-Chi3L1 mAbs partially restored hepatic insulin sensitivity which was associated with reduced lipid accumulation in hepatocytes as well. A KO of the Chi3L1 gene reduced lipid accumulation and improved insulin signaling. Therefore, Chi3L1 gene upregulation may be an important factor in the generation of NAFLD/NASH phenotype.
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Affiliation(s)
- Songhua Zhang
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Aryanna Sousa
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Mengqui Lin
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Ayako Iwano
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Rishubh Jain
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Bing Ma
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
| | - Chang Min Lee
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
| | - Jin Wook Park
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
| | - Suchitra Kamle
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
| | - Rolf Carlson
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Ghun Geun Lee
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
| | - Jack A. Elias
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02912, USA
| | - Jack R. Wands
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
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Chudtong M, Gaetano AD. A mathematical model of food intake. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2021; 18:1238-1279. [PMID: 33757185 DOI: 10.3934/mbe.2021067] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The metabolic, hormonal and psychological determinants of the feeding behavior in humans are numerous and complex. A plausible model of the initiation, continuation and cessation of meals taking into account the most relevant such determinants would be very useful in simulating food intake over hours to days, thus providing input into existing models of nutrient absorption and metabolism. In the present work, a meal model is proposed, incorporating stomach distension, glycemic variations, ghrelin dynamics, cultural habits and influences on the initiation and continuation of meals, reflecting a combination of hedonic and appetite components. Given a set of parameter values (portraying a single subject), the timing and size of meals are stochastic. The model parameters are calibrated so as to reflect established medical knowledge on data of food intake from the National Health and Nutrition Examination Survey (NHANES) database during years 2015 and 2016.
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Affiliation(s)
- Mantana Chudtong
- Department of Mathematics, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
- Center of Excellence in Mathematics, the Commission on Higher Education, Si Ayutthaya Rd., Bangkok 10400, Thailand
| | - Andrea De Gaetano
- Department of Mathematics, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
- Consiglio Nazionale delle Ricerche, Istituto per la Ricerca e l'Innovazione Biomedica (CNR-IRIB), Palermo, Italy
- Consiglio Nazionale delle Ricerche, Istituto di Analisi dei Sistemi ed Informatica "A. Ruberti" (CNR-IASI), Rome, Italy
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40
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Telci EA, Aslan UB, Yagci N, Cavlak U, Kabul EG, Kara G, Kose T, Yarar F, Karahan S, Atalay OT. The Turkish version of the Neck Bournemouth Questionnaire in patients with chronic neck pain: a cultural adaptation, reliability, and validity study. Arch Med Sci 2021; 17:708-713. [PMID: 34025841 PMCID: PMC8130469 DOI: 10.5114/aoms.2019.89322] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 03/28/2018] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION The cultural adaptation of a self-report measurement in different languages is important for developing common strategies for evaluation and treatment. The Neck Bournemouth Questionnaire (NBQ), which was developed to evaluate patients with neck pain, was adapted from the Bournemouth Questionnaire in accordance with the International Classification of Functioning, Disability and Health (ICF) categories. The aim of this study was to conduct the Turkish cultural adaptation, validity and reliability study of the NBQ. MATERIAL AND METHODS The study included 119 patients (93 females, 26 males; mean age: 37.2 ±11.8 years) with chronic nonspecific neck pain. The NBQ, Neck Disability Index (NDI) and Nottingham Health Profile (NHP) questionnaires were administered to all the subjects. Test-retest reliability (intraclass correlation coefficient) and the internal consistency (Cronbach's α) were the methods used for the reliability study. The relationship between NBQ, NDI and NHP was investigated for concurrent validity. Exploratory and confirmatory factor analysis was used for construct validity. RESULTS The Neck Bournemouth Questionnaire showed good internal consistency (α = 0.87). The test-retest reliability coefficient was 0.913 (95% CI: 0.875-0.940). The correlations between NBQ and NDI and NHP were significant (p < 0.05). The questionnaire was found to have one factor and the explained variance was 59.084% as a result of factor analysis. CONCLUSIONS The Neck Bournemouth Questionnaire is a valid and reliable scale for patients with chronic neck pain in the Turkish population.
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Affiliation(s)
| | | | - Nesrin Yagci
- School of Physical Therapy, Pamukkale University, Denizli, Turkey
| | - Ugur Cavlak
- Department of Physiotherapy and Rehabilitation, Avrasya University, Trabzon, Turkey
| | - Elif Gur Kabul
- School of Physical Therapy, Pamukkale University, Denizli, Turkey
| | - Guzin Kara
- School of Physical Therapy, Pamukkale University, Denizli, Turkey
| | | | - Feride Yarar
- School of Physical Therapy, Pamukkale University, Denizli, Turkey
| | - Sevilay Karahan
- Faculty of Medicine, Department of Biostatistics, Hacettepe University, Ankara, Turkey
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R M, Mani S, Sali VK, Bhardwaj M, Vasanthi HR. Macrotyloma uniflorum a plant food alleviates the metabolic syndrome through modulation of adipokines and PPARs. J Food Biochem 2020; 45:e13595. [PMID: 33368458 DOI: 10.1111/jfbc.13595] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/06/2020] [Accepted: 11/30/2020] [Indexed: 11/27/2022]
Abstract
A sedentary lifestyle combined with the intake of high-calorie diet has been the paramount cause of metabolic syndrome (MS) which is now a serious concern of public health worldwide as it involves the coexistence of hypertension, hyperlipidemia, glucose intolerance, and obesity. Hence, identifying a suitable strategy to overcome the worldwide menace of MS is imperative. Macrotyloma uniflorum a lesser known legume is highly nutritious and notable for its ethano-medicinal potential. Herein, the influence of M. uniflorum in high-fat dietinduced metabolic changes in a rodent model of metabolic syndrome was evaluated. Serum levels of glucose, total cholesterol, triglycerides, VLDL-c, and bodyweight were decreased, whereas HDL-c was increased in M. uniflorum-treated MS rats. The protein expression (AMPK-α, PPAR-α, and PPAR-γ) and gene expression (leptin, adiponectin, resistin, UCP2, NF-κB, and IL-6) results are impressive to highlight that M. uniflorum modulates the pathological conditions of MS and proves to be cardioprotective. Furthermore, the histopathological analysis confirmed the pathological changes and substantiates the influence of M. uniflorum to overcome MS. The HPLC and GC (MS) profiling reveals the presence of an array of polyphenols such as rutin (694.61 μg/g), catechin (500.12 μg/g), epicatechin (158.10 μg/g), gallic acid (17.98 μg/g), ferulic acid (10.911 μg/g), daidzein (6.51 μg/g), and PUFA, respectively, which probably exhibits the therapeutic effect on MS and associated complications by modulating lipid metabolism and adipogenesis. PRACTICAL APPLICATIONS: Metabolic disorders like CVD and diabetes are leading cause of mortality and morbidity worldwide. With emerging issues on adverse effects of modern drugs, the emphasis on "Food is Medicine and Medicine as Food" has taken dramatic dimensions in the healthcare sector. Therefore, nutraceuticals are in great demand in the developed world off late. Legumes, are potent elements in a balanced diet next to cereals. Exploring the medicinal properties of legumes could bring a revolution in public health and nutraceutical industries. This study scientifically validated the phytochemicals in M. uniflorum for its functional potential in the management of Metabolic Syndrome (MS). This study would help the nutraceutical industries to develop functional foods using M. uniflorum seeds to make porridges and soups or nutraceutical supplements with the bioflavonoids isolated from M. uniflorum for the management of metabolic disorders by mitigating hyperlipidemia, oxidative stress, and inflammation.
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Affiliation(s)
- Malarvizhi R
- Natural Products Research Laboratory, Department of Biotechnology, School of Life Sciences, Pondicherry University, Puducherry, India
| | - Sugumar Mani
- Natural Products Research Laboratory, Department of Biotechnology, School of Life Sciences, Pondicherry University, Puducherry, India
| | - Veeresh K Sali
- Natural Products Research Laboratory, Department of Biotechnology, School of Life Sciences, Pondicherry University, Puducherry, India
| | - Meenakshi Bhardwaj
- Natural Products Research Laboratory, Department of Biotechnology, School of Life Sciences, Pondicherry University, Puducherry, India
| | - Hannah R Vasanthi
- Natural Products Research Laboratory, Department of Biotechnology, School of Life Sciences, Pondicherry University, Puducherry, India
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De Munck TJI, Xu P, Vanderfeesten BLJ, Elizalde M, Masclee AAM, Nevens F, Cassiman D, Schaap FG, Jonkers DMAE, Verbeek J. The Role of Brown Adipose Tissue in the Development and Treatment of Nonalcoholic Steatohepatitis: An Exploratory Gene Expression Study in Mice. Horm Metab Res 2020; 52:869-876. [PMID: 33260239 DOI: 10.1055/a-1301-2378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Brown adipose tissue (BAT) might be a beneficial mediator in the development and treatment of nonalcoholic steatohepatitis (NASH). We aim to evaluate the gene expression of BAT activity-related genes during the development and the dietary and surgical treatment of NASH. BAT was collected from male C57BL/6J mice that received a high fat-high sucrose diet (HF-HSD) or a normal chow diet (NCD) for 4 and 20 weeks (n=8-9 per dietary group and timepoint) and from mice that underwent dietary intervention (return to NCD) (n=8), roux-en-y gastric bypass (RYGB) (n=6), or sham procedure (n=6) after 12 weeks HF-HSD. Expression of BAT genes involved in lipid metabolism (Cd36 and Cpt1b; p<0.05) and energy expenditure (Ucp1 and Ucp3; p<0.05) were significantly increased after 4 weeks HF-HSD compared with NCD, whereas in the occurrence of NASH after 20 weeks HF-HSD no difference was observed. We observed no differences in gene expression regarding lipid metabolism or energy expenditure at 8 weeks after dietary intervention (no NASH) compared with HF-HSD mice (NASH), nor in mice that underwent RYGB compared with SHAM. However, dietary intervention and RYGB both decreased the BAT gene expression of inflammatory cytokines (Il1b, Tnf-α and MCP-1; p<0.05). Gene expression of the batokine neuregulin 4 was significantly decreased after 20 weeks HF-HSD (p<0.05) compared with NCD, but was restored by dietary intervention and RYGB (p<0.05). In conclusion, BAT is hallmarked by dynamic alterations in the gene expression profile during the development of NASH and can be modulated by dietary intervention and bariatric surgery.
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Affiliation(s)
- Toon J I De Munck
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Pan Xu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Brechtje L J Vanderfeesten
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Montserrat Elizalde
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Ad A M Masclee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Frederik Nevens
- Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
| | - David Cassiman
- Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
| | - Frank G Schaap
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Daisy M A E Jonkers
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Jef Verbeek
- Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
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AlZaim I, Hammoud SH, Al-Koussa H, Ghazi A, Eid AH, El-Yazbi AF. Adipose Tissue Immunomodulation: A Novel Therapeutic Approach in Cardiovascular and Metabolic Diseases. Front Cardiovasc Med 2020; 7:602088. [PMID: 33282920 PMCID: PMC7705180 DOI: 10.3389/fcvm.2020.602088] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 10/22/2020] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue is a critical regulator of systemic metabolism and bodily homeostasis as it secretes a myriad of adipokines, including inflammatory and anti-inflammatory cytokines. As the main storage pool of lipids, subcutaneous and visceral adipose tissues undergo marked hypertrophy and hyperplasia in response to nutritional excess leading to hypoxia, adipokine dysregulation, and subsequent low-grade inflammation that is characterized by increased infiltration and activation of innate and adaptive immune cells. The specific localization, physiology, susceptibility to inflammation and the heterogeneity of the inflammatory cell population of each adipose depot are unique and thus dictate the possible complications of adipose tissue chronic inflammation. Several lines of evidence link visceral and particularly perivascular, pericardial, and perirenal adipose tissue inflammation to the development of metabolic syndrome, insulin resistance, type 2 diabetes and cardiovascular diseases. In addition to the implication of the immune system in the regulation of adipose tissue function, adipose tissue immune components are pivotal in detrimental or otherwise favorable adipose tissue remodeling and thermogenesis. Adipose tissue resident and infiltrating immune cells undergo metabolic and morphological adaptation based on the systemic energy status and thus a better comprehension of the metabolic regulation of immune cells in adipose tissues is pivotal to address complications of chronic adipose tissue inflammation. In this review, we discuss the role of adipose innate and adaptive immune cells across various physiological and pathophysiological states that pertain to the development or progression of cardiovascular diseases associated with metabolic disorders. Understanding such mechanisms allows for the exploitation of the adipose tissue-immune system crosstalk, exploring how the adipose immune system might be targeted as a strategy to treat cardiovascular derangements associated with metabolic dysfunctions.
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Affiliation(s)
- Ibrahim AlZaim
- Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon
- Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
| | - Safaa H. Hammoud
- Department of Pharmacology and Therapeutics, Beirut Arab University, Beirut, Lebanon
| | - Houssam Al-Koussa
- Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon
| | - Alaa Ghazi
- Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon
| | - Ali H. Eid
- Department of Pharmacology and Therapeutics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Department of Basic Medical Sciences, College of Medicine, Qatar University, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
| | - Ahmed F. El-Yazbi
- Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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Escalona-Garrido C, Vázquez P, Mera P, Zagmutt S, García-Casarrubios E, Montero-Pedrazuela A, Rey-Stolle F, Guadaño-Ferraz A, Rupérez FJ, Serra D, Herrero L, Obregon MJ, Valverde ÁM. Moderate SIRT1 overexpression protects against brown adipose tissue inflammation. Mol Metab 2020; 42:101097. [PMID: 33049408 PMCID: PMC7600394 DOI: 10.1016/j.molmet.2020.101097] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 10/02/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Metainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is necessary to find strategies to protect BAT against the effects of inflammation in energy balance. In this study, we explored the impact of moderate sirtuin 1 (SIRT1) overexpression on insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. METHODS The effect of inflammation on BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected with a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies on differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophage-derived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), and norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. RESULTS BAT from the db/db mice was susceptible to metabolic inflammation manifested by the activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance, and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in the lean WT mice upon LPS injection. In contrast, BAT from the mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPS-induced activation of pro-inflammatory signaling, insulin resistance, and defective thermogenic-related responses upon cold exposure. Importantly, the decline in triiodothyronine (T3) levels in the circulation and intra-BAT after exposure of the WT mice to LPS and cold was markedly attenuated in the SIRT1Tg+ mice. In vitro BA experiments in the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophage-derived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses. CONCLUSIONS This study has ascertained the benefit of the moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by BAT inflammation. Our results have potential therapeutic value in combinatorial therapies for BAT-specific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.
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Affiliation(s)
- Carmen Escalona-Garrido
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), 28029 Madrid, Spain
| | - Patricia Vázquez
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), 28029 Madrid, Spain.
| | - Paula Mera
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, E-28029 Madrid, Spain
| | - Sebastián Zagmutt
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain
| | - Ester García-Casarrubios
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), 28029 Madrid, Spain
| | - Ana Montero-Pedrazuela
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer), Instituto de Salud Carlos III, E-28029 Madrid, Spain
| | - Fernanda Rey-Stolle
- Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universitiy, Urbanización Montepríncipe, Boadilla del Monte, 28660, Madrid, Spain
| | - Ana Guadaño-Ferraz
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer), Instituto de Salud Carlos III, E-28029 Madrid, Spain
| | - Francisco J Rupérez
- Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universitiy, Urbanización Montepríncipe, Boadilla del Monte, 28660, Madrid, Spain
| | - Dolors Serra
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, E-28029 Madrid, Spain
| | - Laura Herrero
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, E-28029 Madrid, Spain
| | - Maria Jesus Obregon
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), 28029 Madrid, Spain
| | - Ángela M Valverde
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), 28029 Madrid, Spain.
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Carson C, Macias-Velasco JF, Gunawardana S, Miranda MA, Oyama S, St Pierre CL, Schmidt H, Wayhart JP, Lawson HA. Brown Adipose Expansion and Remission of Glycemic Dysfunction in Obese SM/J Mice. Cell Rep 2020; 33:108237. [PMID: 33027654 PMCID: PMC7594587 DOI: 10.1016/j.celrep.2020.108237] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/09/2020] [Accepted: 09/15/2020] [Indexed: 12/27/2022] Open
Abstract
We leverage the SM/J mouse to understand glycemic control in obesity. High-fat-fed SM/J mice initially develop poor glucose homeostasis relative to controls. Strikingly, their glycemic dysfunction resolves by 30 weeks of age despite persistent obesity. The mice dramatically expand their brown adipose depots as they resolve glycemic dysfunction. This occurs naturally and spontaneously on a high-fat diet, with no temperature or genetic manipulation. Removal of the brown adipose depot impairs insulin sensitivity, indicating that the expanded tissue is functioning as an insulin-stimulated glucose sink. We describe morphological, physiological, and transcriptomic changes that occur during the brown adipose expansion and remission of glycemic dysfunction, and focus on Sfrp1 (secreted frizzled-related protein 1) as a compelling candidate that may underlie this phenomenon. Understanding how the expanded brown adipose contributes to glycemic control in SM/J mice will open the door for innovative therapies aimed at improving metabolic complications in obesity.
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Affiliation(s)
- Caryn Carson
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave., Saint Louis, MO 63108, USA
| | - Juan F Macias-Velasco
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave., Saint Louis, MO 63108, USA
| | - Subhadra Gunawardana
- Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Ave., Saint Louis, MO 63108, USA
| | - Mario A Miranda
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave., Saint Louis, MO 63108, USA
| | - Sakura Oyama
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave., Saint Louis, MO 63108, USA
| | - Celine L St Pierre
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave., Saint Louis, MO 63108, USA
| | - Heather Schmidt
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave., Saint Louis, MO 63108, USA
| | - Jessica P Wayhart
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave., Saint Louis, MO 63108, USA
| | - Heather A Lawson
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave., Saint Louis, MO 63108, USA.
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46
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Drareni K, Ballaire R, Alzaid F, Goncalves A, Chollet C, Barilla S, Nguewa JL, Dias K, Lemoine S, Riveline JP, Roussel R, Dalmas E, Velho G, Treuter E, Gautier JF, Venteclef N. Adipocyte Reprogramming by the Transcriptional Coregulator GPS2 Impacts Beta Cell Insulin Secretion. Cell Rep 2020; 32:108141. [PMID: 32937117 PMCID: PMC7495095 DOI: 10.1016/j.celrep.2020.108141] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 07/03/2020] [Accepted: 08/21/2020] [Indexed: 01/10/2023] Open
Abstract
Glucose homeostasis is maintained through organ crosstalk that regulates secretion of insulin to keep blood glucose levels within a physiological range. In type 2 diabetes, this coordinated response is altered, leading to a deregulation of beta cell function and inadequate insulin secretion. Reprogramming of white adipose tissue has a central role in this deregulation, but the critical regulatory components remain unclear. Here, we demonstrate that expression of the transcriptional coregulator GPS2 in white adipose tissue is correlated with insulin secretion rate in humans. The causality of this relationship is confirmed using adipocyte-specific GPS2 knockout mice, in which inappropriate secretion of insulin promotes glucose intolerance. This phenotype is driven by adipose-tissue-secreted factors, which cause increased pancreatic islet inflammation and impaired beta cell function. Thus, our study suggests that, in mice and in humans, GPS2 controls the reprogramming of white adipocytes to influence pancreatic islet function and insulin secretion.
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Affiliation(s)
- Karima Drareni
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France.
| | | | - Fawaz Alzaid
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Andreia Goncalves
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Catherine Chollet
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Serena Barilla
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 14157, Sweden
| | - Jean-Louis Nguewa
- Department of Diabetes, Clinical Investigation Centre (CIC-9504), Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Karine Dias
- École Normale Supérieure, PSL Research University, Centre National de la Recherche Scientifique (CNRS), INSERM, Institut de Biologie de l'École Normale Supérieure (IBENS), Plateforme Génomique, Paris, France
| | - Sophie Lemoine
- École Normale Supérieure, PSL Research University, Centre National de la Recherche Scientifique (CNRS), INSERM, Institut de Biologie de l'École Normale Supérieure (IBENS), Plateforme Génomique, Paris, France
| | - Jean-Pierre Riveline
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France; Department of Diabetes, Clinical Investigation Centre (CIC-9504), Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Ronan Roussel
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France; Department of Diabetology, Endocrinology and Nutrition, DHU FIRE, Bichat Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Elise Dalmas
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Gilberto Velho
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Eckardt Treuter
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 14157, Sweden
| | - Jean-François Gautier
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France; Department of Diabetes, Clinical Investigation Centre (CIC-9504), Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Nicolas Venteclef
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France.
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47
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Liu H, Luo J, Guillory B, Chen JA, Zang P, Yoeli JK, Hernandez Y, Lee IIG, Anderson B, Storie M, Tewnion A, Garcia JM. Ghrelin ameliorates tumor-induced adipose tissue atrophy and inflammation via Ghrelin receptor-dependent and -independent pathways. Oncotarget 2020; 11:3286-3302. [PMID: 32934774 PMCID: PMC7476735 DOI: 10.18632/oncotarget.27705] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 07/21/2020] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue (AT) atrophy is a hallmark of cancer cachexia contributing to increased morbidity/mortality. Ghrelin has been proposed as a treatment for cancer cachexia partly by preventing AT atrophy. However, the mechanisms mediating ghrelin's effects are incompletely understood, including the extent to which its only known receptor, GHSR-1a, is required for these effects. This study characterizes the pathways involved in AT atrophy in the Lewis Lung Carcinoma (LLC)-induced cachexia model and those mediating the effects of ghrelin in Ghsr +/+ and Ghsr -/- mice. We show that LLC causes AT atrophy by inducing anorexia, and increasing lipolysis, AT inflammation, thermogenesis and energy expenditure. These changes were greater in Ghsr -/-. Ghrelin administration prevented LLC-induced anorexia only in Ghsr +/+, but prevented WAT lipolysis, inflammation and atrophy in both genotypes, although its effects were greater in Ghsr +/+. LLC-induced increases in BAT inflammation, WAT and BAT thermogenesis, and energy expenditure were not affected by ghrelin. In conclusion, ghrelin ameliorates WAT inflammation, fat atrophy and anorexia in LLC-induced cachexia. GHSR-1a is required for ghrelin's orexigenic effect but not for its anti-inflammatory or fat-sparing effects.
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Affiliation(s)
- Haiming Liu
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Gerontology and Geriatric Medicine, University of Washington Department of Medicine, Seattle, WA, USA.,These authors contributed equally to this work
| | - Jiaohua Luo
- Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.,Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University, Chongqing, China.,These authors contributed equally to this work
| | - Bobby Guillory
- Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Ji-An Chen
- Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.,Department of Health Education, College of Preventive Medicine, Army Medical University, Chongqing, China
| | - Pu Zang
- Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.,Department of Endocrinology, Nanjing Jinling Hospital, Nanjing, China
| | - Jordan K Yoeli
- Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Yamileth Hernandez
- Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Ian In-Gi Lee
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Gerontology and Geriatric Medicine, University of Washington Department of Medicine, Seattle, WA, USA
| | - Barbara Anderson
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Gerontology and Geriatric Medicine, University of Washington Department of Medicine, Seattle, WA, USA
| | - Mackenzie Storie
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Gerontology and Geriatric Medicine, University of Washington Department of Medicine, Seattle, WA, USA
| | - Alison Tewnion
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - Jose M Garcia
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Gerontology and Geriatric Medicine, University of Washington Department of Medicine, Seattle, WA, USA.,Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
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48
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de Mendonça M, Rocha KC, de Sousa É, Pereira BMV, Oyama LM, Rodrigues AC. Aerobic exercise training regulates serum extracellular vesicle miRNAs linked to obesity to promote their beneficial effects in mice. Am J Physiol Endocrinol Metab 2020; 319:E579-E591. [PMID: 32744099 DOI: 10.1152/ajpendo.00172.2020] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
There is a growing body of evidence that extracellular vesicles (EVs) and their cargo of RNA, DNA, and protein are released in the circulation with exercise and might mediate interorgan communication. C57BL6/J male mice were subjected to diet-induced obesity and aerobic training on a treadmill for 8 wk. The effect of aerobic training was evaluated in the liver, muscle, kidney, and white/brown adipose tissue. To provide new mechanistic insight, we profiled miRNA from serum EVs of obese and obese trained mice. We demonstrate that aerobic training changes the circulating EV miRNA profile of obese mice, including decreases in miR-122, miR-192, and miR-22 levels. Circulating miRNA levels were associated with miRNA levels in mouse liver white adipose tissue (WAT). In WAT, aerobically trained obese mice showed reduced adipocyte hypertrophy and increased the number of smaller adipocytes and the expression of Cebpa, Pparg, Fabp4 (adipogenesis markers), and ATP-citrate lyase enzyme activity. Importantly, miR-22 levels negatively correlated with the expression of adipogenesis and insulin sensitivity markers. In the liver, aerobic training reverted obesity-induced steatohepatitis, and steatosis score and Pparg expression were negatively correlated with miR-122 levels. The prometabolic effects of aerobic exercise in obesity possibly involve EV miRNAs, which might be involved in communication between liver and WAT. Our data provide significant evidence demonstrating that aerobic training exercise-induced EVs mediate the effect of exercise on adipose tissue metabolism.
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Affiliation(s)
- Mariana de Mendonça
- Departamento de Farmacologia, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brasil
| | - Karina C Rocha
- Departamento de Farmacologia, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brasil
| | - Érica de Sousa
- Departamento de Farmacologia, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brasil
| | - Beatriz M V Pereira
- Departamento de Farmacologia, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brasil
| | - Lila Missae Oyama
- Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brasil
| | - Alice C Rodrigues
- Departamento de Farmacologia, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brasil
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49
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Kuryłowicz A, Puzianowska-Kuźnicka M. Induction of Adipose Tissue Browning as a Strategy to Combat Obesity. Int J Mol Sci 2020; 21:ijms21176241. [PMID: 32872317 PMCID: PMC7504355 DOI: 10.3390/ijms21176241] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/24/2020] [Accepted: 08/26/2020] [Indexed: 12/25/2022] Open
Abstract
The ongoing obesity pandemic generates a constant need to develop new therapeutic strategies to restore the energy balance. Therefore, the concept of activating brown adipose tissue (BAT) in order to increase energy expenditure has been revived. In mammals, two developmentally distinct types of brown adipocytes exist; the classical or constitutive BAT that arises during embryogenesis, and the beige adipose tissue that is recruited postnatally within white adipose tissue (WAT) in the process called browning. Research of recent years has significantly increased our understanding of the mechanisms involved in BAT activation and WAT browning. They also allowed for the identification of critical molecules and critical steps of both processes and, therefore, many new therapeutic targets. Several non-pharmacological approaches, as well as chemical compounds aiming at the induction of WAT browning and BAT activation, have been tested in vitro as well as in animal models of genetically determined and/or diet-induced obesity. The therapeutic potential of some of these strategies has also been tested in humans. In this review, we summarize present concepts regarding potential therapeutic targets in the process of BAT activation and WAT browning and available strategies aiming at them.
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Affiliation(s)
- Alina Kuryłowicz
- Department of Human Epigenetics, Mossakowski Medical Research Centre PAS, 02-106 Warsaw, Poland;
- Correspondence: ; Tel.: +48-226086591; Fax: +48-226086410
| | - Monika Puzianowska-Kuźnicka
- Department of Human Epigenetics, Mossakowski Medical Research Centre PAS, 02-106 Warsaw, Poland;
- Department of Geriatrics and Gerontology, Medical Centre of Postgraduate Education, 01-826 Warsaw, Poland
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50
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Li YZ, Di Cristofano A, Woo M. Metabolic Role of PTEN in Insulin Signaling and Resistance. Cold Spring Harb Perspect Med 2020; 10:a036137. [PMID: 31964643 PMCID: PMC7397839 DOI: 10.1101/cshperspect.a036137] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Phosphatase and tensin homolog (PTEN) is most prominently known for its function in tumorigenesis. However, a metabolic role of PTEN is emerging as a result of its altered expression in type 2 diabetes (T2D), which results in impaired insulin signaling and promotion of insulin resistance during the pathogenesis of T2D. PTEN functions in regulating insulin signaling across different organs have been identified. Through the use of a variety of models, such as tissue-specific knockout (KO) mice and in vitro cell cultures, PTEN's role in regulating insulin action has been elucidated across many cell types. Herein, we will review the recent advancements in the understanding of PTEN's metabolic functions in each of the tissues and cell types that contribute to regulating systemic insulin sensitivity and discuss how PTEN may represent a promising therapeutic strategy for treatment or prevention of T2D.
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Affiliation(s)
- Yu Zhe Li
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada
| | - Antonio Di Cristofano
- Department of Developmental and Molecular Biology and Medicine (Oncology), Albert Einstein College of Medicine and Albert Einstein Cancer Center, Bronx, New York 10461, USA
| | - Minna Woo
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario M5G 2M9, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, University Health Network/Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 2C4, Canada
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