Molecular Metabolism最新文献

{"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":"2025-11-01","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}

{"title":"Pde5a deficiency prevents diet-induced obesity via adipose cAMP-PKA activation enhancing fat browning","authors":"Federica Campolo ,&nbsp;Ottavia Giampaoli ,&nbsp;Federica Barbagallo ,&nbsp;Biagio Palmisano ,&nbsp;Anna Di Maio ,&nbsp;Francesca Sciarra ,&nbsp;Flavio Rizzo ,&nbsp;Serena Monti ,&nbsp;Sandra Albanese ,&nbsp;Silvia Cardarelli ,&nbsp;Maria Rita Assenza ,&nbsp;Eleonora Poggiogalle ,&nbsp;Adriano Patriarca ,&nbsp;Fabio Sciubba ,&nbsp;Antonio Filippini ,&nbsp;Andrea Lenzi ,&nbsp;Daniele Gianfrilli ,&nbsp;Mauro Giorgi ,&nbsp;Susanna Dolci ,&nbsp;Fabio Naro ,&nbsp;Andrea M. Isidori","doi":"10.1016/j.molmet.2025.102243","DOIUrl":"10.1016/j.molmet.2025.102243","url":null,"abstract":"<div><h3>Objective</h3><div>Cyclic nucleotides are central regulators of adipogenesis and adaptive thermogenesis, with their intracellular concentrations tightly controlled by phosphodiesterases (PDEs). Among them, phosphodiesterase type 5 (PDE5A) regulates cyclic guanosine monophosphate (cGMP) turnover in adipocytes. Although PDE5A inhibition has been explored in diabetes, its role in systemic metabolism remains poorly defined.</div></div><div><h3>Methods</h3><div>We employed different <em>Pde5a</em> knockout mouse models to investigate the impact of PDE5A deficiency on adipose tissue biology and whole-body energy homeostasis. Phenotypic, histological, and metabolic assessments were performed under chow and high-fat diet conditions, with a focus on thermogenic activation, hepatic lipid accumulation, and glucose metabolism.</div></div><div><h3>Results</h3><div>Loss of <em>Pde5a</em> resulted in robust activation of brown adipose tissue and moderate browning of white adipose depots, accompanied by a reduction in hepatic lipid content. Upon high-fat diet challenge, <em>Pde5a</em>-deficient mice exhibited resistance to obesity, improved glucose handling, and enhanced thermogenic capacity. Mechanistically, these protective effects originated from early developmental knockdown of <em>Pde5a</em>, which induced metabolic reprogramming via activation of the cAMP–protein kinase A (PKA) signaling pathway. The convergence of cGMP and cAMP signaling cascades orchestrated systemic metabolic adaptations.</div></div><div><h3>Conclusions</h3><div>Our study identifies PDE5A as a previously unrecognized regulator of thermogenesis and energy balance. Targeting PDE5A may therefore represent a promising adjuvant therapeutic approach for the treatment of metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102243"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006372","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":"Dual leucine zipper-bearing kinase DLK is necessary for cell autonomous regulation of insulin sensitivity","authors":"Hetty N. Wong ,&nbsp;Nathan Qi ,&nbsp;Edward B. Arias ,&nbsp;Kae Won Cho ,&nbsp;Deepak Nihalani ,&nbsp;Gregory D. Cartee ,&nbsp;Lawrence B. Holzman","doi":"10.1016/j.molmet.2025.102244","DOIUrl":"10.1016/j.molmet.2025.102244","url":null,"abstract":"<div><div>Metabolic syndrome and insulin resistance are driven in part by dysregulated signaling through the c-Jun N-terminal kinase (JNK) pathway. The scaffold protein JIP1 and its upstream kinase DLK (dual leucine zipper kinase) form a dynamic signaling complex that modulates JNK activity, yet the physiological role of DLK in glucose metabolism remains undefined. Here, we identify DLK as a critical regulator of insulin sensitivity using three genetically modified mouse models: a hypomorphic DLK allele, a tamoxifen-inducible whole-body DLK knockout, and a high-fat diet–induced obese model with DLK ablation. All models exhibited enhanced insulin sensitivity independent of adiposity, characterized by increased glucose uptake in muscle and adipose tissue, and improved suppression of hepatic glucose production during hyperinsulinemic-euglycemic clamp studies. Mechanistically, we demonstrate that DLK functions in a cell-autonomous manner, limiting insulin signaling through modulation of AKT and IRS1 phosphorylation downstream of insulin stimulation. In cultured myoblasts and fibroblasts, DLK was required for JNK activation and subsequent dampening of insulin signaling. These findings establish DLK as a regulator of whole-body insulin sensitivity, independent of obesity through a JIP-JNK signaling module. The results suggest that targeting DLK could represent a therapeutic strategy for improving insulin sensitivity in metabolic disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102244"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993012","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":"2025-11-01","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":"DYRK1A inhibition restores pancreatic functions and improves glucose metabolism in a preclinical model of type 2 diabetes","authors":"Romane Bertrand ,&nbsp;Stefania Tolu ,&nbsp;Delphine Picot ,&nbsp;Cécile Tourrel-Cuzin ,&nbsp;Ayoub Ouahab ,&nbsp;Julien Dairou ,&nbsp;Emmanuel Deau ,&nbsp;Mattias F. Lindberg ,&nbsp;Laurent Meijer ,&nbsp;Jamileh Movassat ,&nbsp;Benjamin Uzan","doi":"10.1016/j.molmet.2025.102242","DOIUrl":"10.1016/j.molmet.2025.102242","url":null,"abstract":"<div><h3>Objectives</h3><div>Insulin deficiency caused by the loss of β cells and/or impaired insulin secretion is a key factor in the pathogenesis of type 2 diabetes (T2D). The restoration of β cell number and function is thus a promising strategy to combat diabetes. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) has been shown to regulate human β cell proliferation. DYRK1A inhibitors are potential therapeutic tools, due to their ability to induce β cell proliferation. However, their anti-diabetic effects in the complex setting of type 2 diabetes remains unexplored. The aim of this study was to determine the impact of chronic DYRK1A inhibition on the remission of diabetes in pre-diabetic and overtly diabetic Goto-Kakizaki (GK) rats.</div></div><div><h3>Methods</h3><div>We assessed the impact of <em>in vivo</em> treatment with a DYRK1A inhibitor, Leucettinib-92, on β cell proliferation and insulin secretion in GK rats. Further, we evaluated the effects of long-term Leucettinib-92 treatment on the whole-body glucose metabolism in overtly diabetic GK rats through the assessment of fasting and post-absorptive glycemia, glucose tolerance and insulin sensitivity.</div></div><div><h3>Results</h3><div>Short-term <em>in vivo</em> treatment of prediabetic GK rats with Leucettinb-92 stimulated β cell proliferation <em>in vivo</em>, and sustainably prevented the development of overt hyperglycemia. Long-term treatment of adult GK rats with established diabetes increased the β cell mass and reduced basal hyperglycemia. Leucettinib-92 treatment also improved glucose tolerance, and glucose-induced insulin secretion <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>We show that DYRK1A inhibition restores the β cell mass and function in a preclinical model of T2D, leading to the improvement of body's global glucose homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102242"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961608","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":"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}