Molecular Metabolism最新文献

{"title":"Periodic fasting induced reconstitution of metabolic flexibility improves albuminuria in patients with type 2 diabetes","authors":"Alba Sulaj ,&nbsp;Phong B.H. Nguyen ,&nbsp;Gernot Poschet ,&nbsp;Elisabeth Kliemank ,&nbsp;Thomas Fleming ,&nbsp;Lea Henke ,&nbsp;Wiebke Neibig ,&nbsp;Stefan Kopf ,&nbsp;Rüdiger Hell ,&nbsp;Valter D. Longo ,&nbsp;Stephan Herzig ,&nbsp;Peter P. Nawroth ,&nbsp;Michael P. Menden ,&nbsp;Julia Szendroedi","doi":"10.1016/j.molmet.2025.102257","DOIUrl":"10.1016/j.molmet.2025.102257","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic inflexibility has been shown to be associated with type 2 diabetes (T2D) and diabetic nephropathy (DN). However, data are lacking, proving that reconstitution of metabolic flexibility by using a 6-month periodic fasting (PF) regimen may improve albuminuria.</div></div><div><h3>Methods</h3><div>In this post hoc analysis of a randomized-controlled trial, we investigated whether the PF regimen enhanced metabolic flexibility in individuals with T2D and DN showing improvement of albuminuria (responders) compared to non-responders. Participants followed every month either a 5-day fasting-mimicking diet or a Mediterranean diet for 6 months. LC-MS/MS-based comprehensive metabolic profiling was performed in plasma samples before, during, and after the intervention. Changes in metabolomic patterns and enriched signalling pathways were analysed between study groups.</div></div><div><h3>Results</h3><div>PF induced a sustained shift toward enhanced fatty acid oxidation, lipid utilization, and amino acids turnover, particularly in responders. Responders exhibited persistent elevations in short-chain acylcarnitines and cholesteryl esters, indicating more efficient lipid oxidation and tighter integration of lipid metabolism with the tricarboxylic acid cycle. Increased glycine and serine levels suggested enhanced cellular maintenance, a protein-sparing effect, and a metabolic shift favouring lipid over carbohydrate. In contrast, non-responders demonstrated only transient and limited metabolic shifts. Unsupervised clustering identified distinct metabolic response patterns, reinforcing the potential of personalized dietary interventions.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that diet-induced restoration of metabolic flexibility is associated with improved albuminuria in T2D, suggesting broader implications for precise nutritional strategies in diabetes management.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102257"},"PeriodicalIF":6.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176773","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":"Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice","authors":"Lorenzo Da Dalt ,&nbsp;Francesca Fantini ,&nbsp;Giulia Giancane ,&nbsp;Annalisa Moregola ,&nbsp;Silvia Roda ,&nbsp;Monika Svecla ,&nbsp;Silvia Pedretti ,&nbsp;Giovanni Battista Vingiani ,&nbsp;Jiangming Sun ,&nbsp;Andreas Edsfeldt ,&nbsp;Isabel Goncalves ,&nbsp;Patrizia Uboldi ,&nbsp;Elena Donetti ,&nbsp;Andrea Baragetti ,&nbsp;Nico Mitro ,&nbsp;Luca Scorrano ,&nbsp;Giuseppe Danilo Norata","doi":"10.1016/j.molmet.2025.102256","DOIUrl":"10.1016/j.molmet.2025.102256","url":null,"abstract":"<div><h3>Objective</h3><div>Mitochondria are involved in cellular metabolism, energy production, calcium homeostasis, and the synthesis of sterols and bile acids (BAs). Emerging evidence suggests that mitochondrial dynamics including biogenesis, fusion, fission, and mitophagy critically influence cardiometabolic diseases, yet their role in atherogenesis remain poorly understood. Mitochondrial fusion ensures metabolic flexibility and stress adaptation, processes highly relevant to lipid handling and vascular cell plasticity. OPA1, a key regulator of inner mitochondrial membrane fusion, has been implicated in metabolic remodeling and cellular stress responses. We therefore investigated whether modulation of OPA1 expression affects lipid homeostasis and plaque formation in LDL receptor-deficient (LDLR KO) mice and in human carotid atherosclerosis.</div></div><div><h3>Methods</h3><div>OPA1^TG/LDLR KO and OPA1^ΔHep/LDLR KO were fed with a Western-type diet (WTD) for 12 weeks. The development of atherosclerosis was compared to that of LDLR KO mice. In humans, the impact of OPA1 was investigated in asymptomatic and symptomatic subjects from the Carotid Plaque Imaging Project (CPIP) biobank.</div></div><div><h3>Results</h3><div>OPA1^TG/LDLR KO mice showed a significant increase in plasma cholesterol levels mainly in VLDL and LDL fractions. OPA1^TG/LDLR KO display a reduction of unconjugated bile acids and higher percentage of conjugated bile acids leading to an increased lipid adsorption. This phenotype was associated with increased atherosclerosis in the aortic root. OPA1 overexpression also resulted in an altered vascular smooth muscle cell (VSMC) cellular metabolism and differentiation, promoting a shift from a contractile/synthetic phenotype toward a more proliferative and metabolically active state. Concordantly, the deletion of OPA1 in hepatocytes improved systemic lipoprotein metabolism protecting from atherosclerosis. Concordantly in humans, plaque OPA1 mRNA levels are associated with metabolic and smooth muscle cell related pathways.</div></div><div><h3>Conclusions</h3><div>Mitochondrial fusion mediated by OPA1 plays a key role in atherosclerosis by affecting lipoprotein metabolism and vascular smooth muscle cell biology.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102256"},"PeriodicalIF":6.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138101","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":"Insulin evokes release of endozepines from astrocytes of the NTS to modulate glucose metabolism in male rats","authors":"Lauryn E. New ,&nbsp;Niannian Wang ,&nbsp;Holly E. Smith ,&nbsp;Ross Birks ,&nbsp;Shabbir Khan Afridi ,&nbsp;Joanne C. Griffiths ,&nbsp;Ryan Hains ,&nbsp;Jamie Johnston ,&nbsp;Beatrice M. Filippi","doi":"10.1016/j.molmet.2025.102255","DOIUrl":"10.1016/j.molmet.2025.102255","url":null,"abstract":"<div><div>The central nervous system (CNS) plays a key role in regulating metabolic functions, but conditions like obesity and diabetes can disrupt this balance. Within the CNS, the nucleus of the solitary tract (NTS) in the dorsal vagal complex (DVC) senses insulin and regulates feeding behaviour and hepatic glucose production. However, we still know little about which cells in the NTS are sensitive to insulin. We show that in male rats insulin receptors in astrocytes are crucial for the NTS's ability to regulate glucose production in the liver. We demonstrate that insulin evokes the release of endozepines from primary astrocytes and direct infusion of endozepines into the NTS mimics the effects of insulin. Inhibition of the benzodiazepine binding site of GABA_A receptors prevents action of both insulin and endozepines. The effect of endozepines within the NTS is mimicked by GABA_A antagonists and prevented by an agonist, suggesting that insulin prompts astrocytes to release endozepines, which then attenuate GABA_A receptor activity, ultimately reducing glucose production in the liver. We also show that high-fat-diet-induced insulin resistance in the NTS can be circumvented by endozepine administration.</div><div>Our study is the first to show that insulin–dependent release of endozepines from NTS-astrocytes is fundamental to control blood glucose levels.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102255"},"PeriodicalIF":6.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113797","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":"Development of a genetically encoded melanocortin sensor for high sensitivity in vivo imaging","authors":"Yoon Namkung ,&nbsp;Tal Slutzki ,&nbsp;Joao Pedroso ,&nbsp;Xiaohong Liu ,&nbsp;Paul V. Sabatini ,&nbsp;Maia V. Kokoeva ,&nbsp;Stéphane A. Laporte","doi":"10.1016/j.molmet.2025.102254","DOIUrl":"10.1016/j.molmet.2025.102254","url":null,"abstract":"<div><h3>Objective</h3><div>The central melanocortin system, composed of peptides derived from pro-opiomelanocortin (POMC) such as the melanocyte-stimulating hormones (α-, β-, γ-MSH) and melanocortin 4 receptors (MC4R), along with the agouti-related protein (AgRP), plays a pivotal role in controlling energy balance. To elucidate the dynamic role of α-MSH release in regulating appetite, specific, sensitive, and spatiotemporally resolved genetic sensors are required.</div></div><div><h3>Methods</h3><div>The melanocortin 1 receptor (MC1R) scaffold was leveraged for its robust plasma membrane expression, high affinity for melanocortins and low affinity for AgRP to design a α-MSH selective sensor for <em>in vivo</em> use. This was achieved by integrating circularly permuted green fluorescent protein (cpGFP) into the receptor, which we named <strong>Fl</strong>uorescence <strong>A</strong>mplified <strong>Re</strong>ceptor sensor for Melanocortin (FLARE_MC).</div></div><div><h3>Results</h3><div>The FLARE_MC sensor has high potency and selectivity in heterologous and homologous expressing cells for α-MSH and the synthetic melanocortin agonist MTII but not to the inverse agonist AgRP. The sensor exhibited impaired signaling, with reduced G protein activation, no β-arrestin coupling, and failed to internalize upon agonist stimulation. <em>In vitro</em>, FLARE_MC displayed high photostability and reversible photoactivation. These properties suggest that the FLARE_MC is suitable for long-term activity recording in the brain without desensitizing or interfering with endogenous melanocortin receptor signaling. When expressed in the paraventricular nucleus (PVN) of the mouse hypothalamus, the primary site of anorexigenic α-MSH signaling, FLARE_MC demonstrated its effectiveness in detecting changes associated with melanocortin responses <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>FLARE_MC enables the study of melanocortin system in cultured cells and <em>in vivo</em>. This first of its class highly sensitive melanocortin sensor will serve as a valuable tool to advance our understanding of the complex dynamics governing melanocortin-dependent appetite regulation and related processes in the brain.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102254"},"PeriodicalIF":6.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102762","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":"Are we giving too much weight to lean mass loss?","authors":"Jeffery Bolte ,&nbsp;Annie A. Smelter ,&nbsp;Luke Norton","doi":"10.1016/j.molmet.2025.102253","DOIUrl":"10.1016/j.molmet.2025.102253","url":null,"abstract":"<div><div>The global rise in obesity has underscored the critical importance of body composition, particularly the balance between fat mass and lean mass, in determining health outcomes. While excess fat mass is a well-established risk factor for numerous chronic diseases and reduced longevity, lean mass preservation has been widely considered essential for mitigating fall risk and maintaining functional independence. Recent advances in incretin-based weight loss therapies have shown remarkable efficacy in reducing body weight but have raised concerns about the concomitant loss of lean mass. However, emerging evidence suggests that muscle quality – rather than absolute muscle mass – is a more robust predictor of functional capacity and all-cause mortality. Intriguingly, these therapies may enhance muscle quality even while promoting lean mass loss, offering a nuanced perspective on their impact. This review aims to synthesize current evidence on body composition, muscle quality, and weight loss therapies to guide clinicians in tailoring weight loss strategies that optimize both metabolic health and patient outcomes.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102253"},"PeriodicalIF":6.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092167","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":"Comparative transcriptomics of lateral hypothalamic cell types reveals conserved growth hormone-tachykinin dynamics in feeding","authors":"Vindhya Chaganty ,&nbsp;Ruey-Kuang Cheng ,&nbsp;Kimberle Shen ,&nbsp;Na Zhang ,&nbsp;Gaynah Javier Doblado ,&nbsp;Sarah Ong ,&nbsp;Sandra Tan ,&nbsp;Valarie Yu Yan Tham ,&nbsp;Jung-Hwa Choi ,&nbsp;Marnie E. Halpern ,&nbsp;Wei Leong Chew ,&nbsp;Anand Kumar Andiappan ,&nbsp;Sarah Xinwei Luo ,&nbsp;Caroline Lei Wee","doi":"10.1016/j.molmet.2025.102251","DOIUrl":"10.1016/j.molmet.2025.102251","url":null,"abstract":"<div><h3>Objectives</h3><div>The lateral hypothalamus (LH) plays a central role in appetite control, however the functional and evolutionary conservation of its subcircuits remain unclear. This study aimed to define the molecular and cellular identities of zebrafish LH neurons, identify conserved LH cell types across vertebrates, and investigate their roles in appetite regulation.</div></div><div><h3>Methods</h3><div>We performed the Act-seq method of single-cell RNA sequencing in the larval zebrafish LH under food-deprived and voracious feeding states to capture activity-dependent transcriptional signatures. Using integrative comparative transcriptomics, we aligned zebrafish neuronal clusters with a published mouse LH dataset to identify conserved neuronal sub-populations, and performed functional and molecular characterisation of a highly-conserved cell type in both zebrafish and mice.</div></div><div><h3>Results</h3><div>We identified several LH neuronal subtypes in zebrafish that are differentially activated during voracious feeding. Cross-species mapping revealed overlapping cellular clusters, especially for GABAergic neurons. We report a conserved GABAergic cluster co-expressing growth hormone (GH) receptors and tachykinin. In both species, feeding activates these neurons and elevates GH receptor and tachykinin expression. In zebrafish, upstream GH signaling is similarly regulated by feeding state, and acute GH administration both activates this cluster and enhances food intake.</div></div><div><h3>Conclusions</h3><div>These findings uncover a conserved GH receptor-tachykinin LH population which may link metabolic hormone signaling to appetite control. Beyond its established long-term roles in growth and metabolism, we propose that GH exerts acute appetite-enhancing effects through activation of this neuronal pathway. Our comparative LH atlas highlights the evolutionary biology of hypothalamic appetite circuits.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102251"},"PeriodicalIF":6.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065109","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":"The liver clock modulates circadian rhythms in white adipose tissue","authors":"Ivan Vlassakev ,&nbsp;Christina Savva ,&nbsp;Gianluca Renzi ,&nbsp;Hema S. Ilamathi ,&nbsp;Doste R. Mamand ,&nbsp;Jacob G. Smith ,&nbsp;Carolina M. Greco ,&nbsp;Christopher Litwin ,&nbsp;Qing Zhang ,&nbsp;Leandro Velez ,&nbsp;Angela Ma ,&nbsp;Martin O. Bergo ,&nbsp;Oscar P.B. Wiklander ,&nbsp;Pura Muñoz-Cánovez ,&nbsp;Niklas Mejhert ,&nbsp;Marcus Seldin ,&nbsp;Johan L.M. Björkegren ,&nbsp;Paolo Sassone-Corsi ,&nbsp;Kevin B. Koronowski ,&nbsp;Salvador Aznar Benitah ,&nbsp;Paul Petrus","doi":"10.1016/j.molmet.2025.102249","DOIUrl":"10.1016/j.molmet.2025.102249","url":null,"abstract":"<div><div>Circadian rhythms are integral to maintaining metabolic health by temporally coordinating physiology across tissues. However, the mechanisms underlying circadian cross-tissue coordination remain poorly understood. In this study, we uncover a central role for the liver clock in regulating circadian rhythms in white adipose tissue (WAT). Using a hepatocyte-specific <em>Bmal1</em> knockout mouse model, we show that hepatic circadian control modulates lipid metabolism in WAT. In addition, by utilizing a model where functional clocks are restricted to the hepatocytes, we demonstrate that the liver clock alone integrates feeding cues to modulate circadian gene expression in WAT, including <em>Cebpa</em>, a key regulator of adipogenesis. We show that the hepatocyte clock regulates adipocyte <em>Cebpa</em> rhythmicity through secreted proteins. Further investigation identified one of the contributing mediators to be the adaptor protein 14-3-3η (<em>Ywhah</em>). The clinical relevance of the liver clock for systemic metabolic function is supported by human cohort data, which revealed a gene regulatory network, consisting of several clock-controlled liver genes, linked to cardiometabolic risk. These findings provide evidence for how the hepatocyte clock coordinates WAT physiology and highlights the core clock system as a potential therapeutic target to improve cardiometabolic health.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102249"},"PeriodicalIF":6.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065133","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":"Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure","authors":"Andrea R. Ortiz ,&nbsp;Kevin Nay ,&nbsp;Brittany A. Stork ,&nbsp;Adam M. Dean ,&nbsp;Sean M. Hartig ,&nbsp;Cristian Coarfa ,&nbsp;Surafel Tegegne ,&nbsp;Christopher RM. Asquith ,&nbsp;Daniel E. Frigo ,&nbsp;Brian York ,&nbsp;Anthony R. Means ,&nbsp;Mark A. Febbraio ,&nbsp;John W. Scott","doi":"10.1016/j.molmet.2025.102250","DOIUrl":"10.1016/j.molmet.2025.102250","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca²⁺-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity.</div></div><div><h3>Methods</h3><div>Mice with myeloid-specific deletion of <em>Camkk2</em> were generated and challenged with a high-fat diet. Metabolic phenotyping, histological analyses, and transcriptomic profiling were used to assess whole-body metabolism, liver lipid accumulation, and gene expression in macrophages and adipose tissue.</div></div><div><h3>Results</h3><div>Myeloid-specific <em>Camkk2</em> deficiency protected mice from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects were associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure.</div></div><div><h3>Conclusions</h3><div>Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102250"},"PeriodicalIF":6.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058505","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":"Single-nucleus mRNA-sequencing reveals dynamics of lipogenic and thermogenic adipocyte populations in murine brown adipose tissue in response to cold exposure","authors":"Janina Behrens ,&nbsp;Tongtong Wang ,&nbsp;Christoph Kilian ,&nbsp;Anna Worthmann ,&nbsp;Mark A. Herman ,&nbsp;Joerg Heeren ,&nbsp;Lorenz Adlung ,&nbsp;Ludger Scheja","doi":"10.1016/j.molmet.2025.102252","DOIUrl":"10.1016/j.molmet.2025.102252","url":null,"abstract":"<div><h3>Objective and methods</h3><div>Brown adipose tissue (BAT) comprises a heterogeneous population of adipocytes and non-adipocyte cell types. To characterize these cellular subpopulations and their adaptation to cold, we performed single-nucleus mRNA-sequencing (snRNA-seq) on interscapular BAT from mice maintained at room temperature or exposed to acute (24h) or chronic (10 days) cold (6 °C). To investigate the role of the <em>de novo</em> lipogenesis (DNL)-regulating transcription factor carbohydrate response element-binding protein (ChREBP), we analyzed control and brown adipocyte-specific ChREBP knockout mice.</div></div><div><h3>Results</h3><div>We identified different cell populations, including seven brown adipocyte subtypes with distinct metabolic profiles. One of them highly expressed ChREBP and DNL enzymes. Notably, these lipogenic adipocytes were highly sensitive to acute cold exposure, showing a marked depletion in BAT of control mice that was compensated by other brown adipocyte subtypes maintaining DNL. Chronic cold exposure resulted in an expansion of basal brown adipocytes and adipocytes putatively derived from stromal and endothelial precursors. In ChREBP-deficient mice, lipogenic adipocytes were almost absent under all conditions, identifying the transcription factor as a key determinant of this adipocyte subtype. Detailed expression analyses revealed <em>Ttc25</em> as a specific marker of lipogenic brown adipocytes and as a downstream target of ChREBP. Furthermore, pathway and cell–cell interaction analyses implicated a Wnt–ChREBP axis in the maintenance of lipogenic adipocytes, with Wnt ligands from stromal and muscle cells providing instructive cues.</div></div><div><h3>Conclusions</h3><div>Our findings provide a comprehensive atlas of BAT cellular heterogeneity and reveal a critical role for ChREBP in lipogenic adipocyte identity, with implications for BAT plasticity and metabolic function.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102252"},"PeriodicalIF":6.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058568","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":"Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice","authors":"Michaela E. Trautman ,&nbsp;Cara L. Green ,&nbsp;Michael R. MacArthur ,&nbsp;Krittisak Chaiyakul ,&nbsp;Yasmine H. Alam ,&nbsp;Chung-Yang Yeh ,&nbsp;Reji Babygirija ,&nbsp;Isabella James ,&nbsp;Michael Gilpin ,&nbsp;Esther Zelenovskiy ,&nbsp;Madelyn Green ,&nbsp;Ryan N. Marshall ,&nbsp;Alexander Raskin ,&nbsp;Michelle M. Sonsalla ,&nbsp;Victoria Flores ,&nbsp;Judith A. Simcox ,&nbsp;Irene M. Ong ,&nbsp;Kristen C. Malecki ,&nbsp;Cholsoon Jang ,&nbsp;Dudley W. Lamming","doi":"10.1016/j.molmet.2025.102248","DOIUrl":"10.1016/j.molmet.2025.102248","url":null,"abstract":"<div><div>The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, there are some reports that dietary supplementation with extra BCAAs has health benefits. Further, the interactions between sex, genetic background, and dietary isoleucine levels in response to a Western Diet (WD) remain incompletely understood. Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 – and we find that in humans, plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, an analysis of human NHANES data shows that isoleucine content varies widely across foods, and that individuals with higher Healthy Eating Index scores tend to consume lower amounts of isoleucine. Our results suggest that the dietary level of isoleucine is a potential mediator of the metabolic and molecular response to a WD, and imply that reducing dietary isoleucine may represent a theoretically translatable strategy to protect from the negative metabolic consequences of a WD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102248"},"PeriodicalIF":6.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054381","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}