Molecular Metabolism最新文献

{"title":"Constructing chimeric mouse islets to study alpha- and delta-cell influence on beta-cell feature","authors":"Alexis Fouque ,&nbsp;Masaya Oshima ,&nbsp;Nina Mode ,&nbsp;Romain Ducellier ,&nbsp;Delphine Thibaut ,&nbsp;Florence Gbahou ,&nbsp;Latif Rachdi ,&nbsp;Over Cabrera ,&nbsp;Raphaël Scharfmann","doi":"10.1016/j.molmet.2025.102245","DOIUrl":"10.1016/j.molmet.2025.102245","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to evaluate the role of alpha- and delta-cell signals on beta-cells within pancreatic mouse islets. Specifically, we investigated how these signals regulate glucose sensitivity, gene expression and function in beta-cells.</div></div><div><h3>Methods</h3><div>We first implemented our previous protocol to FACS purify alpha-, beta-, and delta-cells by adding CD81 as a positive marker for alpha-cells. We next developed an approach to reaggregate these sorted cell populations, creating chimeric islets with different proportions of each endocrine cell type. We used these chimeric islets to study the effect of alpha- and delta-cells on glucose sensitivity, gene expression and function in beta-cells.</div></div><div><h3>Results</h3><div>We generated chimeric islets containing either all three endocrine cell types, alpha- + beta-cells or only beta-cells. We demonstrate that beta-cell glucose sensitivity and identity are independent of signals from alpha- and delta-cells. We identified a subset of genes including Pro-dynorphin, Fumarate hydratase and Txnip whose expression in beta-cells depends on alpha-cells signals acting through the glucagon- and glucagon-like peptide receptors. Finally, we demonstrated that in mouse beta-cell, KCl-mediated insulin secretion relies on an activation of the glucagon-receptor, while glucose-stimulated insulin secretion depends on glucagon-like peptide receptor activation.</div></div><div><h3>Conclusions</h3><div>We developed an innovative and easy-to-use model to reconstruct chimeric islets containing different frequencies of alpha-, beta- and delta-cells. Through this approach, we provide new insights into the complex regulatory mechanisms governing the role of alpha and delta cells on beta-cell features within islets.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102245"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993046","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":"Adipose tissue macrophage-derived miR-690 modulates adipocyte precursor cell maintenance and adipogenesis","authors":"Karina Cunha e Rocha ,&nbsp;Breanna Tan ,&nbsp;Julia Kempf ,&nbsp;Cristina Medina ,&nbsp;Varsha Beldona ,&nbsp;Chengjia Qian ,&nbsp;Ying Duan ,&nbsp;Qian Xiang ,&nbsp;Ahjin Yoo ,&nbsp;Xiaomi Du ,&nbsp;Amit R. Majithia ,&nbsp;Wei Ying","doi":"10.1016/j.molmet.2025.102246","DOIUrl":"10.1016/j.molmet.2025.102246","url":null,"abstract":"<div><div>Obesity is intricately linked to various metabolic diseases; however, some individuals maintain metabolic health despite being classified as obese. A critical factor underlying this paradox is the expansion of white adipose tissue (WAT), which can occur through two mechanisms: hypertrophy (the enlargement of existing fat cells) and hyperplasia (the formation of new fat cells from adipocyte precursor cells, or APCs). Hyperplasia is regarded as a healthier mode of WAT expansion, as it tends to reduce inflammation and protect against insulin resistance. Thus, interventions that promote hyperplasia over hypertrophy could improve metabolic health in obese individuals. In this study, we investigate the role of microRNA-690 (miR-690), an anti-inflammatory and insulin-sensitizing molecule, in maintaining the APC population and facilitating the healthy expansion of epididymal WAT (eWAT). Our findings indicate that in lean mice, macrophages support the APC population by transferring miR-690 to APCs. However, during obesity, the recruitment of pro-inflammatory lipid-associated macrophages (LAMs) to eWAT diminishes miR-690 delivery to APCs, impairing adipogenesis and leading to unhealthy WAT expansion. We demonstrate that strategies aimed at increasing the availability of miR-690 to APCs or mimicking its effects can restore APC functionality. Additionally, mutations in Nadk, the target of miR-690, were shown to mitigate the adverse effects of obesity on APC maintenance in eWAT. These findings suggest that targeting the miR-690-Nadk axis in APCs may provide novel therapeutic strategies to promote healthy adipose tissue expansion and protect against obesity-related metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102246"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006335","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":"2025-11-01","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":"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":"2025-11-01","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":"Suppression of adipocyte ABHD6 favors anti-inflammatory and adipogenic programs to preserve adipose tissue fitness in obesity","authors":"Pegah Poursharifi ,&nbsp;Camille Attané ,&nbsp;Isabelle Chenier ,&nbsp;Clemence Schmitt ,&nbsp;Roxane Lussier ,&nbsp;Anfal Al-Mass ,&nbsp;Yat Hei Leung ,&nbsp;Abel Oppong ,&nbsp;Élizabeth Dumais ,&nbsp;Nicolas Flamand ,&nbsp;Mohamed Abu-Farha ,&nbsp;Jehad Abubaker ,&nbsp;Fahd Al-Mulla ,&nbsp;Ying Bai ,&nbsp;Dongwei Zhang ,&nbsp;Marie-Line Peyot ,&nbsp;André Tchernof ,&nbsp;S.R. Murthy Madiraju ,&nbsp;Marc Prentki","doi":"10.1016/j.molmet.2025.102241","DOIUrl":"10.1016/j.molmet.2025.102241","url":null,"abstract":"<div><div>Some individuals exhibit metabolically healthy obesity, characterized by the expansion of white adipose tissue (WAT) without associated complications. The monoacylglycerol (MAG) hydrolase α/β-hydrolase domain-containing 6 (ABHD6) has been implicated in energy metabolism, with its global deletion conferring protection against obesity. However, the immunometabolic roles of adipocyte ABHD6 in WAT remodeling in response to nutri-stress and obesity are not known. Here, we demonstrate that in insulin resistant women, <em>ABHD6</em> mRNA expression is elevated in visceral fat and positively correlates with obesity and metabolic dysregulation. ABHD6 expression is also elevated in the WATs of diet-induced obese and <em>db/db</em> mice. Although adipocyte-specific ABHD6 knockout (AA-KO) mice become obese under high-fat diet, they show higher plasma adiponectin, reduced circulating insulin and inflammatory markers, improved insulin sensitivity, and lower plasma and liver triglycerides. They also show enhanced insulin action in various tissues, but normal glucose tolerance. In addition, AA-KO mice display healthier and less inflamed expansion of visceral fat, with smaller adipocytes and higher stimulated lipolysis and fatty acid oxidation levels. Similar but less prominent phenotype was found in the subcutaneous and brown fat depots. Thus, adipocyte ABHD6 suppression prevents most of the metabolic and inflammatory complications of obesity, but not obesity <em>per se</em>. Mechanistically, this beneficial process involves a rise in MAG levels in mature adipocytes, and their secretion, resulting in a crosstalk among adipocytes, preadipocytes and macrophages in the adipose microenvironment. Elevated intracellular MAG causes PPARs activation in adipocytes, and MAG secreted from adipocytes curtails the inflammatory polarization of macrophages and promotes preadipocyte differentiation. Hence, adipocyte ABHD6 and MAG hydrolysis contribute to unhealthy WAT remodeling and expansion in obesity, and its suppression represents a candidate strategy to uncouple obesity from many of its immunometabolic complications.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102241"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961659","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":"2025-11-01","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":"Apolipoprotein E receptor 2 in endothelium promote glucose tolerance by mediating insulin delivery to skeletal muscle","authors":"Anastasia Sacharidou ,&nbsp;Ken L. Chambliss ,&nbsp;Jun Peng ,&nbsp;Keiji Tanigaki ,&nbsp;Md Nurul Islam ,&nbsp;Shashank Sirsi ,&nbsp;Andrew Lemoff ,&nbsp;Kenneth Hoyt ,&nbsp;Chieko Mineo ,&nbsp;Philip W. Shaul","doi":"10.1016/j.molmet.2025.102238","DOIUrl":"10.1016/j.molmet.2025.102238","url":null,"abstract":"<div><h3>Objective</h3><div>The delivery of circulating insulin to skeletal muscle myocytes is a rate-limiting step in peripheral insulin action, and there is minimal understanding of the underlying mechanisms in endothelial cells. Recognizing that the LDL receptor family member apolipoprotein E receptor 2 (ApoER2, also known as LRP8) mediates apolipoprotein E (ApoE)-induced signaling in endothelial cells, the present project determined if endothelial ApoER2 influences glucose homeostasis in mice.</div></div><div><h3>Methods</h3><div>Mice were generated deficient in ApoER2 selectively in endothelial cells, and glucose homeostasis was studied. Insulin-stimulated recruitment of the skeletal muscle microvasculature was assessed using contrast-enhanced ultrasound imaging. Endothelial cell insulin uptake and transcytosis were evaluated in culture. The ApoER2 interactome in endothelial cells was interrogated using immunoprecipitation and liquid chromatography/tandem mass spectrometry. ApoER2 structure–function was studied by mutagenesis.</div></div><div><h3>Results</h3><div>Mice deficient in endothelial cell ApoER2 are glucose intolerant and insulin resistant due to a blunting of skeletal muscle glucose disposal that is related to a decrease in muscle insulin delivery. Endothelial ApoER2 manipulation does not alter direct insulin action on skeletal muscle or insulin-stimulated recruitment of the skeletal muscle microvasculature. Instead, ApoER2 stimulation by apolipoprotein E3 (ApoE3) increases endothelial cell insulin uptake and transcytosis. ApoE3 and ApoER2 stimulation of endothelial insulin transport require the ApoER2 adaptor protein Dab2 and the scaffolding protein IQGAP1, which is known to mediate insulin secretion by pancreatic β cells. IQGAP1 is not required for ApoE3/ApoER2-induced insulin uptake by endothelial cells; alternatively it is necessary for insulin transcytosis. ApoE3 prompts IQGAP1 recruitment to the exocyst complex, and ApoER2 interaction with IQGAP1 is necessary for the recruitment.</div></div><div><h3>Conclusions</h3><div>In endothelial cells the ApoE3 and ApoER2 tandem co-opts the role of IQGAP1 in pancreatic β cell insulin secretion to enhance endothelial insulin transport. In this manner endothelial ApoER2 promotes glucose disposal in skeletal muscle and supports normal glucose homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102238"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000984","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":"Regulation of food intake by Connexin43 via adipocyte-sensory neuron electrical synapses","authors":"Xi Chen ,&nbsp;Xing Fang ,&nbsp;Hong Zhou ,&nbsp;Jieyi Meng ,&nbsp;Yang He ,&nbsp;Leon G. Straub ,&nbsp;Andrew Lemoff ,&nbsp;Clair Crewe ,&nbsp;Shangang Zhao ,&nbsp;Yong Xu ,&nbsp;Yi Zhu","doi":"10.1016/j.molmet.2025.102247","DOIUrl":"10.1016/j.molmet.2025.102247","url":null,"abstract":"<div><h3>Background and objective</h3><div>Connexin43 (Cx43), encoded by <em>Gja1</em>, forms gap junctions between adjacent cells. In adipose tissue, it is upregulated during adipose beiging while downregulated by high-fat-diet (HFD) feeding. Adipocyte-specific <em>Gja1</em> overexpression enhances adipose tissue beiging in response to mild cold stress of room temperature. Moreover, those mice display a surprising decrease in food intake, but the mechanism remains unclear. This study investigates how adipocyte Cx43 influences feeding behavior.</div></div><div><h3>Methods</h3><div>Mice with adipose tissue-specific <em>Gja1</em> overexpression (Adipoq-Cx43) were fed with HFD. Food intake, weight gain, substrate utilization, and serum lipolysis were assessed. RNA-seq, proteomics, and cytokine measurements were employed to identify candidate signals. Sensory neurons were manipulated via subcutaneous capsaicin injection or iWAT-targeted optogenetics. Co-culture of adipocytes and sensory neurons in vitro was used to test gap junction communication between these two types of cells.</div></div><div><h3>Results</h3><div>Adipoq-Cx43 mice showed reduced food intake, fat mass, and weight gain on HFD, and shifted substrate utilization toward fatty acids. Although GDF15 was elevated, its neutralization did not reverse the reduced food intake. Instead, systemic ablation of sensory neurons using capsaicin abolished the suppressed food intake. Ooptogenetic activation of sensory neurons in iWAT acutely reduced food intake and improved glucose tolerance after two weeks. In the co-culture of adipocytes and in vitro differentiated sensory neurons, optogenetic stimulation of adipocytes enhanced firing of the adjacent sensory neurons via gap junctions, an effect blocked by the gap junction inhibitor carbenoxolone.</div></div><div><h3>Conclusions</h3><div>Gap junction–mediated electrical communication between adipocytes and sensory neurons may regulate feeding.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102247"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015882","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":"2025-11-01","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":"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":"2025-11-01","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}