Molecular Metabolism最新文献

{"title":"Furin may contribute to proglucagon processing and glucagon-like Peptide-1 production in human alpha cells","authors":"Janyne Koepke,&nbsp;Wentong Long,&nbsp;Amy Barr,&nbsp;Peter E. Light","doi":"10.1016/j.molmet.2025.102259","DOIUrl":"10.1016/j.molmet.2025.102259","url":null,"abstract":"<div><h3>Objectives</h3><div>While glucagon-like peptide-1 (GLP-1) production has been previously documented in human alpha cells, the steps regulating its production and secretion are poorly characterized. We investigated the enzymes implicated in proglucagon processing, characterizing their expression and localization in primary human alpha cells and αTC1/9 cells.</div></div><div><h3>Methods</h3><div>Human alpha cells and αTC1/9 cells were maintained in control conditions or exposed to proinflammatory and Akt-activating stimuli to enhance GLP-1 levels. Proglucagon and convertase enzyme gene expression, protein content, and subcellular localization were evaluated by qPCR, Western Blot, and immunofluorescent microscopy, respectively.</div></div><div><h3>Results</h3><div>Our data suggests that the canonical GLP-1-producing enzyme, Prohormone Convertase 1/3 (PC1/3), is poorly expressed and localized in alpha cells, while its homologue furin is optimally positioned for GLP-1 production. We also note that GLP-1 and glucagon processing occur in different subcellular compartments, creating two distinct pools of secretory granules which respond to similar secretory stimuli.</div></div><div><h3>Conclusion</h3><div>Our study suggests that furin, rather than PC1/3, is positioned to process proglucagon into GLP-1, and despite coming from the same precursor molecule, GLP-1 and glucagon are separately packaged in primary human alpha cells.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102259"},"PeriodicalIF":6.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192112","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":"Dax1 in AgRP neurons regulates thermogenesis via GR-HDAC3-mediated CRFR1 suppression","authors":"Zhuodu Wei ,&nbsp;Jooseon Cha ,&nbsp;Seunghee Lee","doi":"10.1016/j.molmet.2025.102258","DOIUrl":"10.1016/j.molmet.2025.102258","url":null,"abstract":"<div><h3>Objectives</h3><div>The arcuate nucleus of the hypothalamus plays a pivotal role in metabolic homeostasis by integrating the functions of AgRP and POMC neurons. Dax1, a nuclear receptor-like transcription factor, is highly enriched in AgRP neurons; however, its role in energy balance regulation remains largely unexplored. Here, we demonstrate the function of Dax1 in hypothalamic AgRP neurons and its contribution to systemic energy homeostasis and thermogenesis in mice.</div></div><div><h3>Methods</h3><div>We generated AgRP neuron-specific Dax1 conditional knockout mice and assessed their physiological and metabolic responses under high-fat diet feeding and cold exposure. Energy expenditure, brown adipose tissue (BAT) thermogenesis, neuronal activation, and neuropeptide expression were evaluated. Molecular mechanisms were investigated by gene expression analysis, chromatin immunoprecipitation, and biochemical assays.</div></div><div><h3>Results</h3><div>We show that conditional deletion of Dax1 in AgRP neurons enhances energy expenditure, stimulates BAT thermogenesis, and confers resistance to diet-induced obesity in female mice. Notably, these mice exhibit blunted AgRP neuron activation upon cold challenge. Mechanistically, corticotropin-releasing factor receptor type 1 (CRFR1), a key regulator of AgRP neuronal excitability, was upregulated in Dax1-deficient AgRP neurons. We further identified that Dax1 recruits the HDAC3 corepressor complex to the glucocorticoid receptor at the glucocorticoid response element within the <em>Crfr1</em> promoter, thereby repressing <em>Crfr1</em> transcription in response to glucocorticoid signaling.</div></div><div><h3>Conclusions</h3><div>Our findings establish Dax1 as a critical transcriptional repressor of <em>Crfr1</em> in AgRP neurons, linking hypothalamic steroid signaling to the regulation of adaptive thermogenesis and systemic energy balance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102258"},"PeriodicalIF":6.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192137","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":"Weight loss reverses obesity-associated impairments in acute gastrointestinal stretch-induced suppression of food intake and glucose homeostasis","authors":"Maigen Bethea ,&nbsp;Tyler Cook ,&nbsp;Marwa Mommandi ,&nbsp;Andrew McClennan ,&nbsp;Allison Martin ,&nbsp;Jasmine J. Hendrix ,&nbsp;Chelsea R. Hutch ,&nbsp;Alfor Lewis ,&nbsp;Randy J. Seeley ,&nbsp;Henning Fenselau ,&nbsp;Silvania da Silva Teixeria ,&nbsp;Darleen A. Sandoval","doi":"10.1016/j.molmet.2025.102260","DOIUrl":"10.1016/j.molmet.2025.102260","url":null,"abstract":"<div><h3>Objective</h3><div>Chemical and mechanical signals from the gastrointestinal tract are critical for regulating satiety and glucose metabolism. While both nutrient sensing in the intestine and gastric distension has been well studied, the role of intestinal stretch in these metabolic processes remain unclear. This study evaluates the role of intestinal stretch in regulating food intake and glucose homeostasis in the context of normal body weight, obesity, and weight loss occurring via both dietary intervention and vertical sleeve gastrectomy (VSG).</div></div><div><h3>Methods</h3><div>We used the nonnutritive substance mannitol to selectively induce intestinal stretch in conscious mice. We assessed food intake, glucose tolerance, and neuronal activation in mice with normal body weight, obesity, or after dietary or surgically-induced weight loss. We employed chemogenetic approaches to inhibit GLP-1R and OxtR-expressing vagal afferents, and genetic and pharmacological strategies to ablate GLP-1 signaling to explore mechanisms for mannitol-induced suppression of feeding.</div></div><div><h3>Results</h3><div>Mannitol-induced intestinal stretch acutely suppressed food intake and improved oral glucose tolerance independent of GLP-1 signaling and vagal intestinal mechanosensation. Diet induced obesity impairs mannitol-induced intestinal stretch reductions in food intake and attenuates neuronal activation in the nucleus of the solitary tract (NTS) upon induction of intestinal stretch. Both dietary and surgical weight loss restored intestinal stretch-induced feeding suppression and enhanced NTS neuronal activation. Importantly, VSG heightened NTS neuronal activation in response to oral but not IP glucose.</div></div><div><h3>Conclusions</h3><div>Together, these data demonstrate that intestinal stretch contributes to the regulation of feeding and glucose metabolism independently of intestinal nutrient-sensing or classical gut hormones.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102260"},"PeriodicalIF":6.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182172","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":"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}