Metabolism: clinical and experimental最新文献

{"title":"Disruption of mitochondria-associated membranes contributes to the dysregulation of insulin secretion in undernutrition, obesity, and double burden of malnutrition","authors":"Thiago dos Reis Araujo ,&nbsp;Joel Alves da Silva Junior ,&nbsp;Bruna Lourençoni Alves ,&nbsp;Dimitrius Santiago Passos Simões Fróes Guimarães ,&nbsp;Lohanna Monali Barreto ,&nbsp;Mariana Roberta Rodrigues Muniz ,&nbsp;Jennifer Rieusset ,&nbsp;Everardo Magalhães Carneiro","doi":"10.1016/j.metabol.2025.156393","DOIUrl":"10.1016/j.metabol.2025.156393","url":null,"abstract":"<div><h3>Aims/hypothesis</h3><div>Nutritional disorders directly affect the endocrine pancreas, increasing the susceptibility to type 2 diabetes mellitus. However, the molecular mechanisms underlying these alterations remain unknown. This study aims to characterize the role of endoplasmic reticulum (ER)-mitochondria contact sites, known as mitochondrial-associated membranes (MAMs), in insulin secretion dysfunctions associated with undernutrition, obesity, and the double burden of malnutrition (DBM).</div></div><div><h3>Methods</h3><div>Rat pancreatic INS-1E β-cells were cultured in a medium without amino acids supplemented with 1 × (control) or 0.25 × (amino acid restriction) of an amino acid solution for 48 h, and then cells were exposed to a fatty acid mix for 48 h. Male C57BL/6 mice were fed a normoprotein diet (14 % protein) or protein-restricted diet (6 % protein) for 6 weeks and subsequently a high-fat diet (35 % kcal) for 12 weeks. ER-mitochondria interactions were evaluated by in situ proximity ligation assay and transmission electronic microscopy.</div></div><div><h3>Results</h3><div>Our findings indicate that protein restriction reduces ER-mitochondria contacts in pancreatic beta-cells, leading to decreased mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). In contrast, obesity increases ER-mitochondria contact points, mitochondrial metabolism, and GSIS in pancreatic beta-cells, without alterations in viability. DBM results in a significant increase in ER-mitochondria contacts, elevated mitochondrial calcium levels, increased production of reactive oxygen species, and cell death, collectively contributing to impaired GSIS response in the context of obesity.</div></div><div><h3>Conclusions/interpretation</h3><div>These data indicates that MAMs play a crucial role in GSIS during nutritional disorders such as undernutrition, obesity, and DBM. Importantly, changes in MAMs precede GSIS impairment, therefore targeting these interactions might prevent further disruption in beta-cell function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156393"},"PeriodicalIF":11.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"27-Hydroxycholesterol exacerbates hepatic insulin resistance via plasma membrane cholesterol remodeling","authors":"Jinni Yang ,&nbsp;Xue Yang ,&nbsp;Yuan Zheng ,&nbsp;Anhui Wang ,&nbsp;Ziwen Kong ,&nbsp;Qinwen Xiao ,&nbsp;Yuan Tian ,&nbsp;Haijuan Dong ,&nbsp;Zunjian Zhang ,&nbsp;Min Wang ,&nbsp;Rui Song","doi":"10.1016/j.metabol.2025.156392","DOIUrl":"10.1016/j.metabol.2025.156392","url":null,"abstract":"<div><h3>Background and aims</h3><div>Insulin resistance is a key driver of metabolic disorders, yet its molecular mechanisms remain elusive. This study identifies 27-hydroxycholesterol (27HC), a cholesterol-derived metabolite, and investigates its role in insulin resistance.</div></div><div><h3>Methods</h3><div>Targeted metabolomics quantified absolute and relative levels of 27HC (27HC/cholesterol ratio) in patients, mice, and hepatocytes. Insulin resistant mouse models were established to characterize spatiotemporal dynamics of 27HC and related enzymes. Functional analyses assessed 27HC's effect on insulin signaling across multiple hepatocyte types. Transcriptomic analysis identified key effector pathways. Plasma membrane cholesterol accessibility was evaluated using biosensors and validated by cholesterol rescue. Membrane protein extraction, immunofluorescence, and flow cytometry were employed to assess the impact of 27HC on insulin receptor (IR) distribution and binding capacity.</div></div><div><h3>Results</h3><div>Elevated 27HC levels were observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), obese and type 2 diabetic mice (T2DM), and PA-treated HepG2 and primary hepatocytes, correlating with impaired insulin sensitivity. CYP27A1 was identified as the key enzyme regulating liver 27HC levels. In vitro studies demonstrated that 27HC disrupts insulin signaling in HepG2, AML12, and primary hepatocytes, whereas CYP27A1 knockdown restored IR responsiveness. 27HC suppresses SREBP2-dependent cholesterol biosynthesis, depleting accessible cholesterol in the plasma membrane, triggering IR mislocalization and signal attenuation. Liver-specific CYP27A1 silencing in mice fed a high-fat diet improved systemic insulin sensitivity and restored metabolic homeostasis.</div></div><div><h3>Conclusion</h3><div>Our findings establish 27HC as a key effector linking cholesterol metabolism to insulin resistance and propose CYP27A1 inhibition as a potential therapeutic strategy for insulin resistance.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156392"},"PeriodicalIF":11.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship of GDF15 with hepatic mitochondrial respiration is depending on the presence of fibrosis in obese individuals","authors":"Anna Giannakogeorgou ,&nbsp;Sabine Kahl ,&nbsp;Cesare Granata ,&nbsp;Geronimo Heilmann ,&nbsp;Lucia Mastrototaro ,&nbsp;Bedair Dewidar ,&nbsp;Pavel Bobrov ,&nbsp;Irene Esposito ,&nbsp;Aslihan Yavas ,&nbsp;Sandra Trenkamp ,&nbsp;Frank A. Granderath ,&nbsp;Matthias Schlensak ,&nbsp;Christos S. Mantzoros ,&nbsp;Michael Roden ,&nbsp;Patrick Schrauwen","doi":"10.1016/j.metabol.2025.156391","DOIUrl":"10.1016/j.metabol.2025.156391","url":null,"abstract":"<div><h3>Background and purpose</h3><div>Preclinical studies reported elevated growth differentiation factor 15 (GDF15) when mitochondrial function is reduced. In humans, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) exhibit different hepatic mitochondrial adaptation. We hypothesized that circulating GDF15 differently correlates with hepatic mitochondrial respiration in obesity and/or MASLD/MASH.</div></div><div><h3>Methods</h3><div>Humans without (<em>n</em> = 20) and with biopsy-confirmed MASLD (n = 20) or MASH (n = 20) underwent hyperinsulinemic-euglycemic clamps to assess whole-body (M-value) and adipose-tissue (insulin-induced NEFA suppression) insulin sensitivity. Fasting serum GDF15 and glucagon were quantified by ELISA. Mitochondrial respiration was measured in liver obtained during bariatric surgery by high-resolution respirometry. Associations were assessed with Spearman's nonparametric correlation.</div></div><div><h3>Results</h3><div>Serum GDF15 correlated negatively with M-value (<em>r</em> = −0.35, <em>p</em> = 0.017) and NEFA suppression (<em>r</em> = −0.29, <em>p</em> = 0.046), but not with hepatic mitochondrial respiration across the whole cohort. However, correlations were found upon stratification into groups based on the presence (<em>n</em> = 37, age: 41 ± 2y, BMI: 49 ± 1 kg/m²) or absence of hepatic fibrosis (<em>n</em> = 23, 44 ± 2 years, BMI: 49 ± 1 kg/m²). In persons without fibrosis, GDF15 correlated positively with fatty acid oxidation-linked (F_P; <em>r</em> = 0.35, <em>p</em> = 0.035) and maximal coupled (FNS_P; <em>r</em> = 0.42, <em>p</em> = 0.010) mitochondrial respiration. Conversely, GDF15 correlated negatively with hepatic FN_P in persons with fibrosis (<em>r</em> = −0.48, <em>p</em> = 0.022).</div></div><div><h3>Conclusions</h3><div>In humans with obesity, serum GDF15 correlates positively with hepatic mitochondrial respiration in persons without, but negatively in persons with hepatic fibrosis. Future studies are needed to investigate whether and how GDF15 affects hepatic mitochondrial respiration in a fibrosis-dependent manner and/or, conversely, how fibrosis might modulate hepatic GDF15 secretion through altered mitochondrial function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156391"},"PeriodicalIF":11.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SerpinA3N in leptin-sensitive neurons is required for energy and glucose homeostasis and autonomic regulation","authors":"Deng Fu Guo ,&nbsp;Zili Luo ,&nbsp;Alexis Olson ,&nbsp;Donald A. Morgan ,&nbsp;Elizabeth A. Newell ,&nbsp;Kamal Rahmouni","doi":"10.1016/j.metabol.2025.156387","DOIUrl":"10.1016/j.metabol.2025.156387","url":null,"abstract":"<div><h3>Aims</h3><div>SerpinA3N (Serpin peptidase inhibitor clade A member 3) is a serine protease inhibitor upregulated in the hypothalamus by leptin and obesity, yet its role in physiological regulation remains poorly understood. This study aims to elucidate the role of hypothalamic SerpinA3N in regulation of energy balance, glucose homeostasis, and autonomic and cardiovascular functions.</div></div><div><h3>Methods and results</h3><div>Immunostaining revealed that SerpinA3N is primarily expressed in neurons, including those expressing the leptin receptor (LepRb). Targeted deletion of SerpinA3N in LepRb neurons reduced body weight and adiposity and improved insulin sensitivity in female mice. SerpinA3N deficiency also enhanced leptin sensitivity, evidenced by amplified leptin-induced anorexia, weight loss, and LepRb signaling in the hypothalamic arcuate nucleus. Upon exposure to an obesogenic diet, mice lacking SerpinA3N in LepRb neurons exhibited attenuated weight gain, hepatic lipid accumulation and microgliosis. Notably, SerpinA3N deletion in LepRb neurons impaired baroreflex sensitivity and elevated renal sympathetic nerve activity, with dietary obesity further exacerbating sympathetic tone.</div></div><div><h3>Conclusions</h3><div>These findings identify neuronal SerpinA3N as a key regulator of energy balance, leptin and insulin sensitivity, and autonomic function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156387"},"PeriodicalIF":11.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulating metabolism to improve the therapeutic outcomes of CAR cell therapies: From bench to bedside","authors":"Dengxiong Li ,&nbsp;Jie Wang ,&nbsp;Ruicheng Wu ,&nbsp;Qingxin Yu ,&nbsp;Fanglin Shao ,&nbsp;Dilinaer Wusiman ,&nbsp;Zhipeng Wang ,&nbsp;Zhouting Tuo ,&nbsp;Luxia Ye ,&nbsp;Yiqing Guo ,&nbsp;Koo Han Yoo ,&nbsp;Zhihong Liu ,&nbsp;William C. Cho ,&nbsp;Dechao Feng","doi":"10.1016/j.metabol.2025.156375","DOIUrl":"10.1016/j.metabol.2025.156375","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) cell therapies have emerged as a groundbreaking approach in cancer treatment, offering new hope for patients with refractory tumors. Despite their success, the therapeutic efficacy of CAR cell therapies is often undermined by metabolic factors within the tumor microenvironment (TME), which impede CAR cell function and lead to treatment resistance. Current literature has not fully explored how these metabolic processes contribute to CAR cell therapy failure, particularly in the context of solid tumors, where the TME presents unique challenges. Addressing this gap is crucial for enhancing the effectiveness of CAR cell therapies across a broader range of cancers. Here, we review the latest research on the metabolic mechanisms that influence CAR cell therapy outcomes, from preclinical studies to clinical applications. We conducted a comprehensive analysis of studies from PubMed and Web of Science, focusing on how various metabolic processes—such as hypoxia, immune cytokine signaling, glycolysis, adenine metabolism, cellular senescence, lactic acid increment, and cholesterol metabolism—affect CAR cell functions, including cytotoxicity, proliferation, stemness, and activation. Additionally, we examine how interactions between CAR cells and other components of the TME, such as tumor cells, stromal cells, and the extracellular matrix, contribute to an immune-suppressive environment that diminishes CAR cell efficacy. We also discuss potential strategies for overcoming these metabolic barriers, including the development of CAR cells with enhanced metabolic regulation, gene expression modulation, and the combination of CAR cell therapy with existing pharmacological treatments. Our findings underscore the critical role of metabolism in shaping the anti-tumor efficacy of CAR cell therapies in both hematologic and solid tumors. By targeting metabolic pathways within the TME, it is possible to enhance CAR cell infiltration, function, and persistence, thereby overcoming resistance and improving therapeutic outcomes. This approach not only addresses a key limitation in current CAR cell therapies but also paves the way for more effective cancer treatments in the future.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156375"},"PeriodicalIF":11.9,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1” [Metabolism, Volume 163 (2025), Article Number 156087]","authors":"Teresa Mezza ,&nbsp;Nicolai J. Wewer Albrechtsen ,&nbsp;Gianfranco Di Giuseppe ,&nbsp;Pietro Manuel Ferraro ,&nbsp;Laura Soldovieri ,&nbsp;Gea Ciccarelli ,&nbsp;Michela Brunetti ,&nbsp;Giuseppe Quero ,&nbsp;Sergio Alfieri ,&nbsp;Enrico Celestino Nista ,&nbsp;Antonio Gasbarrini ,&nbsp;Vincenzo Tondolo ,&nbsp;Andrea Mari ,&nbsp;Alfredo Pontecorvi ,&nbsp;Andrea Giaccari ,&nbsp;Jens J. Holst","doi":"10.1016/j.metabol.2025.156372","DOIUrl":"10.1016/j.metabol.2025.156372","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"172 ","pages":"Article 156372"},"PeriodicalIF":11.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Syndecan-1 regulates lipid metabolism and mitigates fibrosis during the transition from acute kidney injury to chronic kidney disease","authors":"Daoqi Shen ,&nbsp;Liyu Lin ,&nbsp;Yiqi Su ,&nbsp;Ying Huang ,&nbsp;Yaqiong Wang ,&nbsp;Jiarui Xu ,&nbsp;Wuhua Jiang ,&nbsp;Zhen Zhang ,&nbsp;Xiaoqiang Ding ,&nbsp;Xialian Xu","doi":"10.1016/j.metabol.2025.156374","DOIUrl":"10.1016/j.metabol.2025.156374","url":null,"abstract":"<div><h3>Background</h3><div>The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is characterized by persistent renal fibrosis, in which abnormal lipid metabolism plays a crucial role. Syndecan-1 (SDC-1) has been implicated in various tissue remodeling processes; however, its role in lipid metabolism and fibrosis during the progression from AKI to CKD is not well understood.</div></div><div><h3>Methods</h3><div>This study used a murine model of unilateral ischemia-reperfusion-induced AKI-to-CKD progression for in vivo analysis and employed transforming growth factor-beta (TGF-β)-induced fibrosis in Human Kidney-2 cells and primary mouse tubular epithelial cells for in vitro studies. The tubule-specific knockout and overexpression of SDC-1 mice were utilized to investigate kidney fibrosis and lipid metabolism.</div></div><div><h3>Results</h3><div>Following unilateral ischemia-reperfusion and TGF-β stimulation, SDC-1 expression was significantly reduced, exacerbating renal fibrosis. Notably, SDC-1 deficiency led to lipid accumulation in the kidneys, while its overexpression alleviated lipid overload and improved metabolic parameters. Furthermore, SDC-1 played a crucial role in regulating fatty acid-binding protein 7 (FABP7), and its absence resulted in increased FABP7 levels. Inhibition of FABP7 not only reduced fibrosis but also restored carnitine palmitoyltransferase 1α expression, which suggests that the SDC-1/FABP7 axis is critical for maintaining lipid homeostasis and mitigating fibrosis in the kidney.</div></div><div><h3>Conclusion</h3><div>These findings underscore the importance of SDC-1 in lipid metabolism and suggest that targeting lipid metabolic pathways may represent therapeutic strategies that can slow the progression of AKI to CKD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"172 ","pages":"Article 156374"},"PeriodicalIF":11.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Symphony of regulated cell death: Unveiling therapeutic horizons in sarcopenia","authors":"Jie Peng ,&nbsp;Mi Zou ,&nbsp;Qianmingyue Zhang ,&nbsp;Dongcan Liu ,&nbsp;Shuanghong Chen ,&nbsp;Ruiying Fang ,&nbsp;Yuan Gao ,&nbsp;Xiaohua Yan ,&nbsp;Liang Hao","doi":"10.1016/j.metabol.2025.156359","DOIUrl":"10.1016/j.metabol.2025.156359","url":null,"abstract":"<div><div>Sarcopenia is a progressive musculoskeletal condition associated with aging, marked by a decline in muscle mass, strength, and performance. This condition not only compromises functional independence in older individuals but also contributes to escalating healthcare and economic burdens. Although the underlying mechanisms are complex and multifaceted, recent discoveries have emphasized the regulatory influence of multiple forms of programmed cell death—including apoptosis, ferroptosis, necroptosis, and pyroptosis—on skeletal muscle degeneration. These cell death pathways contribute to key pathological features such as muscle fiber loss, proteostasis imbalance, neuromuscular dysfunction, mitochondrial deficits, and persistent inflammation. This review synthesizes current understanding of the molecular underpinnings of regulated cell death (RCD) in sarcopenia and discusses emerging therapeutic interventions aimed at modulating these pathways. These include pharmacological agents (e.g., ferroptosis inhibitors, polyphenols), structured exercise programs (notably resistance), targeted nutritional support (e.g., amino acids, vitamin D), cell-based therapies, and gene-targeted strategies. Despite growing evidence supporting RCD as a viable therapeutic target, the interplay among different cell death modalities and the translation of mechanistic insights into clinical practice remain insufficiently understood. Advancing sarcopenia treatment will require integrated multi-omics analyses, identification of predictive biomarkers, and rigorously designed clinical studies to support personalized and effective therapeutic approaches.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"172 ","pages":"Article 156359"},"PeriodicalIF":11.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The intersection of exercise, nitric oxide, and metabolism: Unraveling the role of eNOS in skeletal muscle and beyond","authors":"Pierre-Anne R. Laird ,&nbsp;Rebecca M. Wall ,&nbsp;Siobhan M. Craige","doi":"10.1016/j.metabol.2025.156360","DOIUrl":"10.1016/j.metabol.2025.156360","url":null,"abstract":"<div><div>Exercise protects against several diseases including cardiometabolic disorders. However, the molecular mechanisms driving these adaptations remain incompletely defined. Endothelial nitric oxide synthase (eNOS), a key source of nitric oxide (NO), is implicated in regulating glucose uptake, fatty acid metabolism, and mitochondrial remodeling in response to exercise. eNOS is expressed in both endothelial and non-endothelial cells and its effects on metabolism are multifaceted. Notably, eNOS is highly expressed in endothelial cells which are ubiquitous throughout all organ systems allowing them to closely integrate with surrounding cell types. This unique feature of the endothelium enables eNOS to influence both local microenvironments and signaling across organ systems. This review summarizes current findings on the role of eNOS-derived NO in exercise metabolism. Evidence suggests eNOS contributes to improved metabolic flexibility, enhanced mitochondrial function, and tissue crosstalk. However, data across experimental models remain mixed, with both supportive and conflicting results. Collectively, the literature indicates that eNOS plays a central, though context-dependent, role in facilitating exercise-induced metabolic benefits. Identifying the specific mechanisms and tissue contributions of eNOS activity remains an important area for future investigation, with potential relevance to metabolic disease prevention and treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156360"},"PeriodicalIF":11.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural selection signatures of 65 syndromic and 8 monogenic obesity genes in 7 ethnic groups do not support the thrifty genotype hypothesis","authors":"Sandra El Kouche ,&nbsp;David Meyre","doi":"10.1016/j.metabol.2025.156353","DOIUrl":"10.1016/j.metabol.2025.156353","url":null,"abstract":"<div><h3>Background</h3><div>The “thrifty genotype hypothesis” states that gene variants promoting efficient fat deposition may have been advantaged by natural selection to allow human survival during famine. Nowadays, such genes are rendered detrimental by progress as they promote fat deposition in preparation for a famine that never comes, resulting in widespread obesity. Obesity is genetically heterogeneous, with a continuum between very rare syndromic, rare monogenic, and common polygenic forms of obesity. The identification of natural selection signatures has been largely restricted to polygenic obesity-susceptibility variants, and this approach has failed to validate the thrifty genotype hypothesis. However, polygenic variants may not be as relevant as monogenic mutations, characterized by strong phenotypic effects on body mass index variation and obesity risk, in detecting significant signatures of natural selection.</div></div><div><h3>Methods</h3><div>We investigated the patterns of natural selection of 65 syndromic and 8 monogenic obesity genes in the gnomAD multiethnic population (N = 807,162).</div></div><div><h3>Results</h3><div>Our data suggest that most dominant syndromic obesity genes display negative signatures of natural selection (i.e., deleterious alleles are selectively purged from the population). In contrast, monogenic obesity genes exhibit neither negative nor positive patterns of natural selection. Our findings do not support the thrifty genotype hypothesis for syndromic and monogenic hyperphagic obesity in 7 ethnic groups.</div></div><div><h3>Conclusion</h3><div>Our work highlights the evolutionary mechanisms that have shaped the modern ethnic distribution of monogenic and syndromic obesity mutations, why some individuals are susceptible to obesity and have a profound impact on therapeutic strategies for managing chronic diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156353"},"PeriodicalIF":11.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}