Molecular Metabolism最新文献

{"title":"Enhanced Metabolic Adaptations Following Late Dark Phase Wheel Running in High-Fat Diet-Fed Mice.","authors":"Stephen P Ashcroft, Amy M Ehrlich, Krzysztof Burek, Logan A Pendergrast, Caio Y Yonamine, Jonas T Treebak, Juleen R Zierath","doi":"10.1016/j.molmet.2025.102116","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102116","url":null,"abstract":"<p><p>Exercise interventions represent an effective strategy to prevent and treat metabolic diseases and the time-of-day-dependent effects of exercise on metabolic outcomes are becoming increasingly apparent. We aimed to study the influence of time-restricted wheel running on whole-body energy and glucose homeostasis. Male, 8-week-old, C57BL/6NTac mice were fed either a 60% high-fat diet (HFD) or a 10% low-fat diet (LFD) for 4 weeks. Following this, mice were given access to a running wheel between zeitgeber time (ZT) 12-16 (early dark phase) or ZT 20-0 (late dark phase). Sedentary mice had access to a permanently locked wheel. Mice were housed under these conditions in metabolic chambers for 4 weeks in which LFD and HFD conditions were maintained. Following the exercise intervention, body composition and glucose tolerance were assessed. Wheel running during either the early or late dark phase resulted in metabolic improvements such as attenuation in body weight gain, enhanced glucose tolerance and reduced ectopic lipid deposition. However, late dark phase exercise resulted in a greater reduction in body weight gain, as well as enhanced metabolic flexibility and insulin sensitivity. Our data suggest that late dark phase versus early dark phase exercise confers greater metabolic adaptations in HFD-fed mice.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102116"},"PeriodicalIF":7.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492934","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":"Renalase inhibition defends against acute and chronic β cell stress by regulating cell metabolism.","authors":"Tara MacDonald, Birgitta Ryback, Jéssica Aparecida da Silva Pereira, Siying Wei, Bryhan Mendez, Erica P Cai, Yuki Ishikawa, Meagan Arbeau, Gordon Weir, Susan Bonner-Weir, Stephan Kissler, Peng Yi","doi":"10.1016/j.molmet.2025.102115","DOIUrl":"10.1016/j.molmet.2025.102115","url":null,"abstract":"<p><p>Renalase (Rnls), annotated as an oxidase enzyme, is a GWAS gene associated with Type 1 diabetes (T1D) risk. We previously discovered that Rnls inhibition delays diabetes onset in mouse models of T1D in vivo, and protects pancreatic β cells against autoimmune killing, ER and oxidative stress in vitro. The molecular biochemistry and functions of Rnls are largely uncharted. Here we find that Rnls inhibition defends against loss of β cell mass and islet dysfunction in chronically stressed Akita mice in vivo. We used RNA sequencing, untargeted and targeted metabolomics and metabolic function experiments in a mouse β cell line and human stem cell-derived β cells and discovered a robust and conserved metabolic shift towards glycolysis to counter protein misfolding stress, in vitro. Our work illustrates metabolic functions for Rnls in mammalian cells and suggests an axis by which manipulating intrinsic properties of β cells can rewire metabolism to protect against diabetogenic stress.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102115"},"PeriodicalIF":7.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483661","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":"BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics","authors":"Se Seul Im ,&nbsp;Jihyeon Seo ,&nbsp;Ji Eun You ,&nbsp;Hye Won Bang ,&nbsp;YongHwan Kim ,&nbsp;Jiyeon Kweon ,&nbsp;Yongsub Kim ,&nbsp;Dong-Myung Shin ,&nbsp;Jaekyoung Son","doi":"10.1016/j.molmet.2025.102113","DOIUrl":"10.1016/j.molmet.2025.102113","url":null,"abstract":"<div><h3>Objectives</h3><div>Increased expression of glutaminase (GLS) has been found to correlate with more aggressive disease and poorer prognosis in patients with several types of cancer, including breast, lung, and pancreatic cancer. G9a histone methyltransferase inhibitors may have anticancer activity. The present study assessed whether BIX01294 (BIX), a G9a histone methyltransferase inhibitor, can inhibit glutaminase (GLS) in pancreatic ductal adenocarcinoma (PDAC) cells.</div></div><div><h3>Methods</h3><div>The effects of BIX on mitochondrial metabolism in PDAC cells were evaluated by targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) metabolomic analysis. To assess the impact of BIX on glutathione dynamics, real-time changes in glutathione levels were monitored by FreSHtracer-based GSH assays.</div></div><div><h3>Results</h3><div>BIX significantly inhibited the growth of PDAC cells, both in vitro and <em>in vivo</em>, and robustly induced apoptotic cell death. BIX significantly increased the cellular NADP⁺/NADPH ratio and decreased the ratio of reduced-to-oxidized glutathione (GSH:GSSG). In addition, BIX decreased GSH levels and increased ROS levels. N-acetyl-<span>l</span>-cysteine (NAC) supplementation dramatically rescued PDAC cells from BIX-induced apoptosis. Furthermore, BIX inhibited the transcription of GLS by inhibiting Jumonji-domain histone demethylases but not G9a histone methyltransferase. One Jumonji-domain histone demethylase, KDM6B, epigenetically regulated GLS expression by binding to the GLS gene promoter.</div></div><div><h3>Conclusions</h3><div>Collectively, these findings suggest that BIX could be a potent therapeutic agent in patients with PDAC through its inhibition of GLS-mediated cellular redox balance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"94 ","pages":"Article 102113"},"PeriodicalIF":7.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441526","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":"The neglected PCK1/glucagon (inter)action in nutrient homeostasis beyond gluconeogenesis: Disease pathogenesis and treatment","authors":"Romina Bertinat ,&nbsp;Todd Holyoak ,&nbsp;Rodrigo Gatica ,&nbsp;Nery Jara ,&nbsp;Iván González-Chavarría ,&nbsp;Francisco Westermeier","doi":"10.1016/j.molmet.2025.102112","DOIUrl":"10.1016/j.molmet.2025.102112","url":null,"abstract":"<div><h3>Background</h3><div>Glucagon plays a central role in hepatic adaptation during fasting, with the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) traditionally associated with increased gluconeogenesis. However, recent experimental models and clinical studies have challenged this view, suggesting a more complex interplay between PCK1 and glucagon, which extends beyond gluconeogenesis and has broader implications for metabolic regulation in health and disease.</div></div><div><h3>Scope of review</h3><div>This review provides a comprehensive overview of the current evidence on the multifaceted roles of PCK1 in glucagon-dependent hepatic adaptation during fasting, which is crucial for maintaining systemic homeostasis not only of glucose, but also of lipids and amino acids. We explore the relationship between PCK1 deficiency and glucagon resistance in metabolic disorders, including inherited PCK1 deficiency and metabolic dysfunction-associated steatotic liver disease (MASLD), and compare findings from experimental animal models with whole-body or tissue-specific ablation of PCK1 or the glucagon receptor. We propose new research platforms to advance the therapeutic potential of targeting PCK1 in metabolic diseases.</div></div><div><h3>Major conclusions</h3><div>We propose that hepatic PCK1 deficiency might be an acquired metabolic disorder linking alterations in lipid metabolism with impaired glucagon signaling. Our findings highlight interesting links between glycerol, PCK1 deficiency, elevated plasma alanine levels and glucagon resistance. We conclude that the roles of PCK1 and glucagon in metabolic regulation are more complex than previously assumed. In this (un)expected scenario, hepatic PCK1 deficiency and glucagon resistance appear to exert limited control over glycemia, but have broader metabolic effects related to lipid and amino acid dysregulation. Given the shift in glucagon research from receptor inhibition to activation, we propose that a similar paradigm shift is needed in the study of hepatic PCK1. Understanding PCK1 expression and activity in the glucagon-dependent hepatic adaptation to fasting might provide new perspectives and therapeutic opportunities for metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"94 ","pages":"Article 102112"},"PeriodicalIF":7.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425709","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":"Corrigendum to “Timing of exercise differentially impacts adipose tissue gain in male adolescent rats” [Mol Metabol 93 (2025) 102100, 1–14]","authors":"Y. Kutsenko ,&nbsp;L.P. Iñiguez ,&nbsp;A. Barreda ,&nbsp;L. Pardo-Marín ,&nbsp;A. Toval ,&nbsp;D. Garrigos ,&nbsp;M. Martínez-Morga ,&nbsp;S. Pujante ,&nbsp;B. Ribeiro Do-Couto ,&nbsp;K.Y. Tseng ,&nbsp;J.J. Cerón ,&nbsp;M. Garaulet ,&nbsp;Wisniewska ,&nbsp;M. Irimia ,&nbsp;J.L. Ferran","doi":"10.1016/j.molmet.2025.102110","DOIUrl":"10.1016/j.molmet.2025.102110","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102110"},"PeriodicalIF":7.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385902","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":"ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance","authors":"Philipp Stüve ,&nbsp;Gloria J. Godoy ,&nbsp;Fernando N. Ferreyra ,&nbsp;Florencia Hellriegel ,&nbsp;Fatima Boukhallouk ,&nbsp;Yu-San Kao ,&nbsp;Tushar H. More ,&nbsp;Anne-Marie Matthies ,&nbsp;Tatiana Akimova ,&nbsp;Wolf-Rainer Abraham ,&nbsp;Volkhard Kaever ,&nbsp;Ingo Schmitz ,&nbsp;Karsten Hiller ,&nbsp;Matthias Lochner ,&nbsp;Benoît L. Salomon ,&nbsp;Ulf H. Beier ,&nbsp;Michael Rehli ,&nbsp;Tim Sparwasser ,&nbsp;Luciana Berod","doi":"10.1016/j.molmet.2025.102111","DOIUrl":"10.1016/j.molmet.2025.102111","url":null,"abstract":"<div><h3>Objective</h3><div>Regulatory T cells (Tregs) are essential in maintaining immune tolerance and controlling inflammation. Treg stability relies on transcriptional and post-translational mechanisms, including histone acetylation at the <em>Foxp3</em> locus and FoxP3 protein acetylation. Additionally, Tregs depend on specific metabolic programs for differentiation, yet the underlying molecular mechanisms remain elusive. We aimed to investigate the role of acetyl-CoA carboxylase 1 (ACC1) in the differentiation, stability, and function of regulatory T cells (Tregs).</div></div><div><h3>Methods</h3><div>We used either T cell-specific ACC1 knockout mice or ACC1 inhibition via a pharmacological agent to examine the effects on Treg differentiation and stability. The impact of ACC1 inhibition on Treg function was assessed <em>in vivo</em> through adoptive transfer models of Th1/Th17-driven inflammatory diseases.</div></div><div><h3>Results</h3><div>Inhibition or genetic deletion of ACC1 led to an increase in acetyl-CoA availability, promoting enhanced histone and protein acetylation, and sustained FoxP3 transcription even under inflammatory conditions. Mice with T cell-specific ACC1 deletion exhibited an enrichment of double positive RORγt⁺FoxP3⁺ cells. Moreover, Tregs treated with an ACC1 inhibitor demonstrated superior long-term stability and an enhanced capacity to suppress Th1/Th17-driven inflammatory diseases in adoptive transfer models.</div></div><div><h3>Conclusions</h3><div>We identified ACC1 as a metabolic checkpoint in Treg biology. Our data demonstrate that ACC1 inhibition promotes Treg differentiation and long-term stability <em>in vitro</em> and <em>in vivo</em>. Thus, ACC1 serves as a dual metabolic and epigenetic hub, regulating immune tolerance and inflammation by balancing <em>de novo</em> lipid synthesis and protein acetylation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"94 ","pages":"Article 102111"},"PeriodicalIF":7.0,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391191","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":"Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasis","authors":"Zuojie Peng ,&nbsp;Jia Song ,&nbsp;Wenzhong Zhu ,&nbsp;Haijun Bao ,&nbsp;Yuan Hu ,&nbsp;Yongping Shi ,&nbsp;Xukai Cheng ,&nbsp;Mi Jiang ,&nbsp;Feifei Fang ,&nbsp;Jinhuang Chen ,&nbsp;Xiaogang Shu","doi":"10.1016/j.molmet.2025.102109","DOIUrl":"10.1016/j.molmet.2025.102109","url":null,"abstract":"<div><h3>Objective</h3><div>There is growing evidence that sleep deprivation promotes cancer progression. In addition, colon cancer patients often experience sleep deprivation due to factors such as cancer pain and side effects of treatment. The occurrence of liver metastases is an important factor in the mortality of colon cancer patients. However, the relationship between sleep deprivation and liver metastases from colon cancer has not been elucidated.</div></div><div><h3>Methods</h3><div>A sleep deprivation liver metastasis model was constructed to evaluate the effect of sleep deprivation on liver metastasis of colon cancer. Subsequently, mice feces were collected for untargeted metabolomics to screen and identify the key mediator, Kynurenic acid (KynA). Furthermore, HILPDA was screened by transcriptomics, and its potential mechanism was explored through ChIP, co-IP, ubiquitination experiments, phenotyping experiments, etc.</div></div><div><h3>Results</h3><div>Sleep deprivation promotes liver metastases in colon cancer. Functionally, sleep deprivation aggravates lipid accumulation and decreases the production of the microbiota metabolite KynA. In contrast, KynA inhibited colon cancer progression <em>in vitro</em>. <em>In vivo</em>, KynA supplementation reversed the promoting effects of sleep deprivation on liver metastases from colon cancer. Mechanistically, KynA downregulates the expression of P4HA2 to promote the ubiquitination and degradation of HIF-1α, which leads to a decrease in the transcription of HILPDA, and ultimately leads to an increase in lipolysis of colon cancer cells.</div></div><div><h3>Conclusions</h3><div>Our findings reveal that sleep deprivation impairs intracellular lipolysis by KynA, leading to lipid droplets accumulation in colon cancer cells. This process ultimately promotes colon cancer liver metastasis. This suggests a promising strategy for colon cancer treatment.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102109"},"PeriodicalIF":7.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374327","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":"Altered thermal preference by preoptic estrogen receptor alpha neurons in postpartum females","authors":"Nan Zhang ,&nbsp;Meng Yu ,&nbsp;Qianru Zhao ,&nbsp;Bing Feng ,&nbsp;Yue Deng ,&nbsp;Jonathan C. Bean ,&nbsp;Qingzhuo Liu ,&nbsp;Benjamin P. Eappen ,&nbsp;Yang He ,&nbsp;Kristine M. Conde ,&nbsp;Hailan Liu ,&nbsp;Yongjie Yang ,&nbsp;Longlong Tu ,&nbsp;Mengjie Wang ,&nbsp;Yongxiang Li ,&nbsp;Na Yin ,&nbsp;Hesong Liu ,&nbsp;Junying Han ,&nbsp;Darah Ave Threat ,&nbsp;Nathan Xu ,&nbsp;Chunmei Wang","doi":"10.1016/j.molmet.2025.102108","DOIUrl":"10.1016/j.molmet.2025.102108","url":null,"abstract":"<div><h3>Objective</h3><div>This study aims to investigate how reproductive experience (RE) alters thermal preference and thermoregulation in female mice, with a focus on estrogen receptor alpha (ERα)-expressing neurons in the preoptic area (POA).</div></div><div><h3>Methods</h3><div>Thermal preference and body temperature were measured in female mice with and without RE, and virgin female mice with selective deletion of ERα from the POA (ERα^POA-KO). The number and activity of ERα-expressing POA neurons (ERα^POA) were assessed using immunohistochemistry and in vitro electrophysiology in response to temperature changes and ERα agonist.</div></div><div><h3>Results</h3><div>We showed that female mice prefer a cooler environment starting from late pregnancy and persisting long term postpartum. Female mice with RE (&gt;4 weeks post-weaning) displayed lower body temperature and a lower thermal preferred temperature, and lost preference for warm environments (30 °C) but preserved avoidance of cold environments (15 °C). This was associated with a significant decrease in the number of ERα^POA neurons. Importantly, virgin female ERα^POA-KO mice displayed lower thermal preferred temperature and impaired warm preference, mimicking RE mice. We further found that distinct ERα^POA subpopulations can be regulated by temperature changes with or without presynaptic blockers, and by ERα agonist. More importantly, RE decreased the number of warm-activated ERα^POA neurons and reduced the excitatory effects of warmth and estrogen-ERα signaling, while cold-activated ERα^POA neurons were slightly enhanced in female mice with RE.</div></div><div><h3>Conclusion</h3><div>Our results support that the thermosensing ability and estrogenic effects in ERα^POA neurons are regulated by reproductive experience, altering thermal preference.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102108"},"PeriodicalIF":7.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256011","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":"HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesis","authors":"Michio Sato ,&nbsp;Tsuyoshi Kadomatsu ,&nbsp;Jun Morinaga ,&nbsp;Yuya Kinoshita ,&nbsp;Daisuke Torigoe ,&nbsp;Haruki Horiguchi ,&nbsp;Sumio Ohtsuki ,&nbsp;Shuji Yamamura ,&nbsp;Ryoko Kusaba ,&nbsp;Takanori Yamaguchi ,&nbsp;Goro Yoshioka ,&nbsp;Kimi Araki ,&nbsp;Tomohiko Wakayama ,&nbsp;Keishi Miyata ,&nbsp;Koichi Node ,&nbsp;Yuichi Oike","doi":"10.1016/j.molmet.2025.102107","DOIUrl":"10.1016/j.molmet.2025.102107","url":null,"abstract":"<div><h3>Objective</h3><div>Cardiac function declines with age, impairing exercise tolerance and negatively impacting healthy aging. However, mechanisms driving age-related declines in cardiac function are not fully understood.</div></div><div><h3>Methods</h3><div>We examined mechanisms underlying age-related cardiac dysfunction using 3- and 24-month-old wild-type mice fed ad libitum or 24-month-old wild-type mice subjected to 70% calorie restriction (CR) starting at 2-month-old. In addition, cardiac aging phenotypes and mitochondrial biogenesis were also analyzed in 25-month-old cardiac-specific Hint1 knockout mice, 24-month-old CAG-Caren Tg mice, and 24-month-old wild-type mice injected with AAV6-Caren.</div></div><div><h3>Results</h3><div>We observed inactivation of mitochondrial biogenesis in hearts of aged mice. We also showed that activity of the BAF chromatin remodeling complex is repressed by HINT1, whose expression in heart increases with age, leading to decreased transcription of Tfam, which promotes mitochondrial biogenesis. Interestingly, CR not only suppressed age-related declines in cardiac function and mitochondrial biogenesis but blocked concomitant increases in cardiac HINT1 protein levels and maintained Tfam transcription. Furthermore, expression of the lncRNA Caren, which inhibits Hint1 mRNA translation, decreased with age in heart, and CR suppressed this effect. Finally, decreased HINT1 expression due to Caren overexpression antagonized age-related declines in mitochondrial biogenesis, ameliorating age-related cardiac dysfunction, exercise intolerance, and exercise-induced cardiac damage and subsequent death of mice.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that mitochondrial biogenesis in cardiomyocytes decreases with age and could underlie cardiac dysfunction, and that the Caren-HINT1-mitochondrial biogenesis axis may constitute a mechanism linking CR to resistance to cardiac aging. We also show that ameliorating declines in mitochondrial biogenesis in cardiomyocytes could counteract age-related declines in cardiac function, and that this strategy may improve exercise tolerance and extend so-called \"healthy life span\".</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102107"},"PeriodicalIF":7.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256019","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":"Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation","authors":"Gianluca Renzi ,&nbsp;Ivan Vlassakev ,&nbsp;Mattias Hansen ,&nbsp;Romane Higos ,&nbsp;Simon Lecoutre ,&nbsp;Merve Elmastas ,&nbsp;Ondrej Hodek ,&nbsp;Thomas Moritz ,&nbsp;Lynn M. Alaeddine ,&nbsp;Scott Frendo–Cumbo ,&nbsp;Ingrid Dahlman ,&nbsp;Alastair Kerr ,&nbsp;Salwan Maqdasy ,&nbsp;Niklas Mejhert ,&nbsp;Mikael Rydén","doi":"10.1016/j.molmet.2024.102082","DOIUrl":"10.1016/j.molmet.2024.102082","url":null,"abstract":"<div><div>In white adipose tissue, disturbed creatine metabolism through reduced creatine kinase B (CKB) transcription contributes to obesity-related inflammation. However, the mechanisms regulating <em>CKB</em> expression in human white adipocytes remain unclear. By screening conditions perturbed in obesity, we identified endoplasmic reticulum (ER) stress as a key suppressor of <em>CKB</em> transcription across multiple cell types. Through follow-up studies, we found that ER stress through the IRE1–XBP1s pathway, promotes <em>CKB</em> promoter methylation via the methyltransferase DNMT3A. This epigenetic change represses <em>CKB</em> transcription, shifting metabolism towards glycolysis and increasing the production of the pro-inflammatory chemokine CCL2. We validated our findings in vivo, demonstrating that individuals living with obesity show an inverse relationship between <em>CKB</em> expression and promoter methylation in white adipocytes, along with elevated CCL2 secretion. Overall, our study uncovers a regulatory axis where ER stress drives inflammation in obesity by reducing CKB abundance, and consequently altering the bioenergetic state of the cell.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102082"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829429","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}