Molecular Metabolism最新文献

{"title":"Excessive Exercise Elicits Poly (ADP-Ribose) Polymerase-1 Activation and Global Protein PARylation Driving Muscle Dysfunction and Performance Impairment.","authors":"Barbara M Crisol, Matheus B Rocha, Beatriz Franco, Ana Paula Morelli, Carlos K Katashima, Scylas J A Junior, Fernanda S Carneiro, Renata R Braga, Rafael S Brícola, Graciana de Azambuja, Raul Gobato Costa, Andrea M Esteves, Marcelo A Mori, Maria C G Oliveira, Dennys E Cintra, José R Pauli, Filip J Larsen, Adelino S R da Silva, Eduardo R Ropelle","doi":"10.1016/j.molmet.2025.102135","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102135","url":null,"abstract":"<p><p>Excessive exercise combined with inadequate recovery time may trigger fatigue, performance impairment, and ultimately the overtraining syndrome. The intramyocellular mechanisms involved in the overtraining syndrome remain only partially known. Here, we combined multi-omics analyses from isogenic BXD mouse strains with a mouse model of overtraining and excessive exercise protocol in mice and humans to evaluate the molecular mechanism involved in the performance impairment induced by excessive exercise. We identified that BXD mouse strains with elevated levels of Parp1 gene expression in the skeletal muscle displayed features like overtraining syndrome and abnormal muscle genetic signature. High PARP1 protein content and aberrant PARylation of proteins were detected in the skeletal muscle of overtrained, but not in trained mice. Overtraining syndrome reduced mitochondrial function promoted by exercise training, induced muscle hyperalgesia, reduced muscle fiber size and promoted a similar gene signature of myopathy and atrophy models. Short periods of excessive exercise also increased PARylation in the skeletal muscle of mice and healthy subjects. The pharmacological inhibition of PARP1, using Olaparib, and genetic Parp1 ablation, preserved muscle anatomy and protected against physical performance impairment and other symptoms of the overtraining syndrome in mice. In conclusion, PARP1 excessive activation is related to muscle abnormalities led by long or short periods of excessive exercise, and here we suggest that PARP1 is a potential target in the treatment and prevention of overtraining syndrome.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102135"},"PeriodicalIF":7.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LOX-1 rewires glutamine ammonia metabolism to drive liver fibrosis.","authors":"Ruihua Huang, Hanyu Cui, Mohammed Abdulaziz Yahya Ali Alshami, Chuankui Fu, Wei Jiang, Mingyuan Cai, Shuhan Zhou, Xiaoyun Zhu, Changping Hu","doi":"10.1016/j.molmet.2025.102132","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102132","url":null,"abstract":"<p><strong>Objective: </strong>Liver fibrosis is a crucial condition for evaluating the prognosis of chronic liver disease. Lectin-1ike oxidized low density lipoprotein receptor-1 (LOX-1) has been shown potential research value and therapeutic targeting possibilities in different fibrotic diseases. However, the role of LOX-1 and the underlying mechanisms in liver fibrosis progression remain unclear.</p><p><strong>Methods: </strong>LOX-1 expression was detected in liver tissues from patients and rodents with liver fibrosis. LOX-1 knockout rats were subjected to CCl₄ or methionine and choline-deficient diet (MCD) to induce liver fibrosis. Transcriptomic and metabolomics analysis were used to investigate the involvement and mechanism of LOX-1 on liver fibrosis.</p><p><strong>Results: </strong>We found that LOX-1 exacerbated liver fibrosis by promoting hepatic stellate cells (HSCs) activation. LOX-1 deletion reversed the development of liver fibrosis. We further verified that LOX-1 drove liver fibrosis by reprogramming glutamine metabolism through mediating isoform switching of glutaminase (GLS). Mechanistically, we revealed the crucial role of the LOX-1/OCT1/GLS1 axis in the pathogenesis of liver fibrosis. Moreover, LOX-1 rewired ammonia metabolism by regulating glutamine metabolism-urea cycle to drive the progression of liver fibrosis.</p><p><strong>Conclusions: </strong>Our findings uncover the pivotal role of LOX-1 in the progression of liver fibrosis, enrich the pathological significance of LOX-1 regulation of hepatic ammonia metabolism, and provide an insight into promising targets for the therapeutic strategy of liver fibrosis, demonstrating the potential clinical value of targeting LOX-1 in antifibrotic therapy.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102132"},"PeriodicalIF":7.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipocyte-derived shed Syndecan-4 suppresses lipolysis contributing to impaired adipose tissue browning and adaptive thermogenesis.","authors":"Jiuyu Zong, Xiaoping Wu, Xiaowen Huang, Lufengzi Yuan, Kai Yuan, Zixuan Zhang, Mengxue Jiang, Zhihui Ping, Lai Yee Cheong, Aimin Xu, Ruby Lai Chong Hoo","doi":"10.1016/j.molmet.2025.102133","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102133","url":null,"abstract":"<p><p>Lipolysis in white adipose tissue (WAT) provides fatty acids as energy substrates for thermogenesis to increase energy expenditure. Syndecan-4 (Sdc4) is a transmembrane proteoglycan bearing heparan sulfate chains. Although single nucleotide polymorphisms (SNPs) of the Sdc4 gene have been identified linking to metabolic syndromes, its specific function in adipose tissue remains obscure. Here, we show that Sdc4 serves as a regulator of lipid metabolism and adaptive thermogenesis. Sdc4 expression and shedding are elevated in the WAT of diet-induced obese mice. Adipocyte-specific deletion of Sdc4 promotes lipolysis and WAT browning, thereby raising whole-body energy expenditure to protect against diet-induced obesity. Mechanistically, fibroblast growth factor 2 (FGF2) is a paracrine factor that maintains energy homeostasis. Elevated shed Sdc4 concentrates and delivers FGF2 to fibroblast growth factor receptor 1 (FGFR1) on adipocytes, which in turn suppresses lipolysis by reducing hormone-sensitive lipase (HSL) activity, thus exaggerating adipose tissue dysfunction upon high-fat diet induction. Sdc4-deficient adipocytes show higher lipolytic and thermogenic capacity by enhancing HSL phosphorylation and UCP1 expression. Overall, our study reveals that adipocyte-derived shed Sdc4 is a novel suppressor of lipolysis, contributing to decreased energy expenditure, thus exaggerating obesity. Targeting shed Sdc4 is a potential therapeutic strategy for obesity.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102133"},"PeriodicalIF":7.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A GLP-1 analogue optimized for cAMP-biased signaling improves weight loss in obese mice.","authors":"Jonathan D Douros, Aaron Novikoff, Barent DuBois, Rebecca Rohlfs, Jacek Mokrosinski, Wouter F J Hogendorf, Robert Augustin, Myrte Merkestein, Lene Brandt Egaa Martini, Lars Linderoth, Elliot Gerrard, Janos Tibor Kodra, Jenny Norlin, Nikolaj Kulahin Roed, Anouk Oldenburger, Stephanie A Mowery, Maria Waldhoer, Diego Perez-Tilve, Brian Finan, Steffen Reedtz-Runge, Timo D Müller, Patrick J Knerr","doi":"10.1016/j.molmet.2025.102124","DOIUrl":"10.1016/j.molmet.2025.102124","url":null,"abstract":"<p><strong>Objective: </strong>Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism is foundational to modern obesity pharmacotherapies. These compounds were engineered for maximal G protein alpha(s) (Gsα) signaling potency and downstream cAMP production. However, this strategy requires reconsideration as partial, biased GLP-1R agonists characterized by decreased Gsα signaling and disproportionate reductions in β-arrestin recruitment relative to the native ligand provide greater weight loss than full, balanced agonists in preclinical models.</p><p><strong>Methods: </strong>We tested the hypothesis that in vitro signaling bias, which considers both cAMP signaling and β-arrestin recruitment, better predicts weight loss efficacy in diet induced obese (DIO) rodents than cAMP potency alone.</p><p><strong>Results: </strong>Our data demonstrate that signaling bias significantly correlates to GLP-1R agonist mediated weight loss in diet-induced obese mice. We further characterized a protracted GLP-1 analogue (NNC5840) which exhibits a partial-Gsα, cAMP-biased GLP-1R signaling profile in vitro and demonstrates superior maximal body weight reduction compared to semaglutide in DIO mice. The NNC5840 weight loss profile is characterized by reduced in vivo potency but increased maximal efficacy.</p><p><strong>Conclusions: </strong>The data demonstrate that biased agonism is a strong predictor of in vivo efficacy for GLP-1R agonists independent of factors like intrinsic cAMP potency or pharmacokinetics. These data suggest that drug discovery screening strategies which take a holistic approach to target receptor signaling may provide more efficacious candidate molecules. The interpretations of these studies are limited by unknowns including how structural modifications to the biased GLP-1R agonist effect physiochemical properties of the molecules.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102124"},"PeriodicalIF":7.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-dependent effects of FGF21 on HPA axis regulation and adrenal regeneration after cushing syndrome in mice.","authors":"Daniela Díaz-Catalán, Júlia Capó, Arturo Vega-Beyhart, Maite Rodrigo, Mireia Mora, Oscar Vidal, Mattia Squarcia, Joaquim Enseñat, Gregori Casals, Felicia Hanzu","doi":"10.1016/j.molmet.2025.102122","DOIUrl":"10.1016/j.molmet.2025.102122","url":null,"abstract":"<p><strong>Background: </strong>Cushing's Syndrome (CS) results from prolonged exposure to excessive glucocorticoids (GCs), leading to metabolic disturbances and adrenal insufficiency (AI). Fibroblast growth factor 21 (FGF21) has shown promise as a potential therapeutic target for metabolic disorders. This study explores the effects of FGF21 on adrenal gland function in a mouse model of AI following chronic hypercortisolism and investigates sex-dependent differences in the hypothalamic-pituitary-adrenal (HPA) axis response.</p><p><strong>Methods: </strong>We employed a mouse model of AI after chronic corticosterone (CORT) treatment. We studied the effects of recombinant human FGF21 (hFGF21) administration on adrenal function in AI mice. We then investigated male and female wild-type (WT) and FGF21-overexpressing transgenic (Tg) mice subjected to 5 weeks of CORT treatment reaching CS phenotype, followed by immediate analysis or a 10-week recovery period. We evaluated metabolic parameters, HPA axis function, and adrenal gland morphology and gene expression.</p><p><strong>Results: </strong>Prolonged CORT exposure resulted in metabolic disturbances and HPA axis dysregulation. hFGF21 treatment increased CORT and ACTH secretion in AI mice. FGF21 overexpression influenced glucose homeostasis and insulin regulation during CORT treatment and recovery, with sex-specific effects. Tissue-specific regulation of Klb expression was observed across the HPA axis, with distinct patterns between males and females. Tg mice displayed altered adrenal progenitor cell activation and steroidogenic gene expression. Sex-specific differences were observed in adrenal capsule remodeling and gene expression patterns during recovery.</p><p><strong>Conclusions: </strong>This study reveals the complex interplay between FGF21 signaling and GC-induced metabolic and endocrine changes, suggesting a potential sex-specific role of FGF21 in the metabolic and HPA after CS.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102122"},"PeriodicalIF":7.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD73 promotes the immunoregulatory functions of hepatic Tregs through enzymatic and nonenzymatic pathways in MASLD development","authors":"Hua Jin ,&nbsp;Xinjie Zhong ,&nbsp;Chunpan Zhang ,&nbsp;Yongle Wu ,&nbsp;Jie Sun ,&nbsp;Xiyu Wang ,&nbsp;Zeyu Wang ,&nbsp;Jingjing Zhu ,&nbsp;Yuan Jiang ,&nbsp;Xiaonan Du ,&nbsp;Zihan Zhang ,&nbsp;Dong Zhang ,&nbsp;Guangyong Sun","doi":"10.1016/j.molmet.2025.102131","DOIUrl":"10.1016/j.molmet.2025.102131","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading chronic liver disease characterized by chronic inflammation. Regulatory T cells (Tregs) highly express CD73 and play a critical role in modulating the immune response. However, the roles and mechanisms by which CD73 modulates Tregs in MASLD are still unknown. A choline-deficient high-fat diet (CDHFD) or methionine/choline-deficient diet (MCD) was used to establish a MASLD model. We found that CD73 expression was upregulated in Tregs via the FFA-mediated p38/GATA2 signaling pathway. <em>Cd73</em> KO promoted MASLD progression, accompanied by decreased Treg viability and activity. Compared with <em>Cd73</em> KO Tregs, adoptively transferred WT Tregs exhibited increased Treg activity and provided greater protection against hepatic inflammatory responses in MASLD. This immune protection is mediated by CD73 via both enzymatic and nonenzymatic pathways, degrading AMP into ADO to increase Treg function and block DR5-TRAIL-mediated cell death signaling. These findings suggest a potential immunotherapeutic approach for MASLD treatment and highlight its possible relevance for clinical application.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102131"},"PeriodicalIF":7.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans.","authors":"Brian Finan, Jonathan D Douros, Ronald Goldwater, Ann Maria Kruse Hansen, Julie B Hjerpsted, Karina Rahr Hjøllund, Martin K Kankam, Patrick J Knerr, Anish Konkar, Stephanie A Mowery, Timo D Müller, John Rømer Nielsen, Sune Boris Nygård, Diego Perez-Tilve, Kirsten Raun, Bin Yang, Matthias H Tschöp, Richard D DiMarchi","doi":"10.1016/j.molmet.2025.102129","DOIUrl":"10.1016/j.molmet.2025.102129","url":null,"abstract":"<p><p>Single molecules that combine complementary modes of action with glucagon-like peptide-1 receptor (GLP-1R) agonism are best-in-class therapeutics for obesity treatment. NN1706 (MAR423, RO6883746) is a fatty-acylated tri-agonist designed for balanced activity at GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR) with lower relative potency at the glucagon receptor (GcgR). Obese mice, rats and non-human primates dosed with NN1706 showed significant body weight reductions and improved glycemic control. In human participants with overweight or obesity, daily subcutaneous NN1706 treatment resulted in substantial body weight loss in a dose-dependent manner without impairing glycemic control (NCT03095807, NCT03661879). However, increased heart rate was observed across NN1706 treatment cohorts, which challenges further clinical development of NN1706.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102129"},"PeriodicalIF":7.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semaglutide and bariatric surgery induce distinct changes in the composition of mouse white adipose tissue","authors":"Margo P. Emont ,&nbsp;Adam L. Essene ,&nbsp;Anton Gulko ,&nbsp;Nadejda Bozadjieva-Kramer ,&nbsp;Christopher Jacobs ,&nbsp;Soumya Nagesh ,&nbsp;Randy J. Seeley ,&nbsp;Linus T. Tsai ,&nbsp;Evan D. Rosen","doi":"10.1016/j.molmet.2025.102126","DOIUrl":"10.1016/j.molmet.2025.102126","url":null,"abstract":"<div><div>Adipose tissue is a central player in energy balance and glucose homeostasis, expanding in the face of caloric overload in order to store energy safely. If caloric overload continues unabated, however, adipose tissue becomes dysfunctional, leading to systemic metabolic compromise in the form of insulin resistance and type 2 diabetes. Changes in adipose tissue during the development of metabolic disease are varied and complex, made all the more so by the heterogeneity of cell types within the tissue. Here we present detailed comparisons of atlases of murine WAT in the setting of diet-induced obesity, as well as after weight loss induced by either vertical sleeve gastrectomy (VSG) or treatment with the GLP-1 receptor agonist semaglutide. We focus on identifying populations of cells that return to a lean-like phenotype versus those that persist from the obese state, and examine pathways regulated in these cell types across conditions. These data provide a resource for the study of the cell type changes in WAT during weight loss, and paint a clearer picture of the differences between adipose tissue from lean animals that have never been obese, versus those that have.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102126"},"PeriodicalIF":7.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical training reduces cell senescence and associated insulin resistance in skeletal muscle","authors":"Agnieszka Podraza-Farhanieh ,&nbsp;Rosa Spinelli ,&nbsp;Federica Zatterale ,&nbsp;Annika Nerstedt ,&nbsp;Silvia Gogg ,&nbsp;Matthias Blüher ,&nbsp;Ulf Smith","doi":"10.1016/j.molmet.2025.102130","DOIUrl":"10.1016/j.molmet.2025.102130","url":null,"abstract":"<div><h3>Background</h3><div>Cell senescence (CS) is a key aging process that leads to irreversible cell cycle arrest and an altered secretory phenotype. In skeletal muscle (SkM), the accumulation of senescent cells contributes to sarcopenia. Despite exercise being a known intervention for maintaining SkM function and metabolic health, its effects on CS remain poorly understood.</div></div><div><h3>Objectives</h3><div>This study aimed to investigate the impact of exercise on CS in human SkM by analyzing muscle biopsies from young, normal-weight individuals and middle-aged individuals with obesity, both before and after exercise intervention.</div></div><div><h3>Methods</h3><div>Muscle biopsies were collected from both groups before and after an exercise intervention. CS markers, insulin sensitivity (measured with euglycemic clamp), and satellite cell markers were analyzed. Additionally, <em>in vitro</em> experiments were conducted to evaluate the effects of cellular senescence on human satellite cells, focusing on key regulatory genes and insulin signaling.</div></div><div><h3>Results</h3><div>Individuals with obesity showed significantly elevated CS markers, along with reduced expression of <em>GLUT4</em> and <em>PAX7</em>, indicating impaired insulin action and regenerative potential. Exercise improved insulin sensitivity, reduced CS markers, and activated satellite cell response in both groups. In vitro experiments revealed that senescence downregulated key regulatory genes in satellite cells and impaired insulin signaling by reducing the Insulin Receptor β-subunit.</div></div><div><h3>Conclusions</h3><div>These findings highlight the role of CS in regulating insulin sensitivity in SkM and underscore the therapeutic potential of exercise in mitigating age- and obesity-related muscle dysfunction. Targeting CS through exercise or senolytic agents could offer a promising strategy for improving metabolic health and combating sarcopenia, particularly in at-risk populations.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102130"},"PeriodicalIF":7.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice","authors":"L. Stilgenbauer ,&nbsp;Q. Chen ,&nbsp;D. Pungi ,&nbsp;N. James ,&nbsp;H. Jayarathne ,&nbsp;L. Koshko ,&nbsp;S. Scofield ,&nbsp;K. Zhang ,&nbsp;M. Sadagurski","doi":"10.1016/j.molmet.2025.102128","DOIUrl":"10.1016/j.molmet.2025.102128","url":null,"abstract":"<div><h3>Background</h3><div>Chronic high-fat diet (HFD) feeding triggers hypothalamic inflammation and systemic metabolic dysfunction associated with endoplasmic reticulum (ER) stress. Glial cells, specifically microglia and astrocytes, are central mediators of hypothalamic inflammation. However, the role of Inositol-Requiring Enzyme 1α (IRE1α), a primary ER stress sensor, in glial cells and its contributions to metabolic dysfunction remains elusive.</div></div><div><h3>Objectives</h3><div>To investigate the role of IRE1α in microglia in mediating HFD-induced metabolic dysfunction.</div></div><div><h3>Methods</h3><div>Using novel conditional knockout mouse models (CX3CR1^GFPΔIRE1 and TMEM119^ERΔIRE1), we deleted IRE1α in immune cells or exclusively in microglia and studied its impact on metabolic health and hypothalamic transcriptional changes in mice fed with HFD for 16 weeks.</div></div><div><h3>Results</h3><div>Deleting IRE1α in microglia significantly reduced LPS-induced pro-inflammatory cytokine gene expression <em>in vitro</em>. IRE1α deletion in microglia protected male mice from HFD-induced obesity, glucose intolerance, and hypothalamic inflammation, with no metabolic benefits observed in female mice. RNA-sequencing revealed significant transcriptional reprogramming of the hypothalamus, including upregulation of genes related to mitochondrial fatty acid oxidation, metabolic adaptability, and anti-inflammatory responses.</div></div><div><h3>Conclusions</h3><div>Our findings reveal that IRE1α-mediated ER stress response in microglia significantly contributes to hypothalamic inflammation and systemic metabolic dysfunction in response to HFD, particularly in males, demonstrating an important role of microglial ER stress response in diet-induced obesity and metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102128"},"PeriodicalIF":7.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}