Molecular Metabolism最新文献

{"title":"Regulating the cell differentiation trajectory of progenitor cells in adipose tissue fibrosis","authors":"Li Zhang ,&nbsp;Xinjiang Cai ,&nbsp;Xiuju Wu ,&nbsp;Zheng Jing ,&nbsp;Yan Zhao ,&nbsp;Yucheng Yao ,&nbsp;Kristina I. Boström","doi":"10.1016/j.molmet.2025.102231","DOIUrl":"10.1016/j.molmet.2025.102231","url":null,"abstract":"<div><h3>Objective</h3><div>Adipose fibrosis signifies pathological remodeling of white adipose tissue (WAT) associated with insulin resistance, diabetes, and cardiovascular disease. Matrix Gla protein (MGP) balances bone morphogenetic protein (BMP) and transforming growth factor β (TGFβ) signaling but has an unclear role in WAT.</div></div><div><h3>Methods</h3><div>To study the role of MGP in WAT, we used mice with global or platelet-derived growth factor receptor α (<em>Pdgfra</em>)-Cre-mediated <em>Mgp</em> deletion in adipose progenitor cells (APCs) together with single cell RNA sequencing (scRNA-seq), characterization on adipose and fibrotic phenotypes, and BMP and TGFβ signaling studies.</div></div><div><h3>Results</h3><div>Our results showed that Mgp deletion promotes fibrosis and impairs adipogenesis in mice with global or <em>Pdgfra</em>-Cre-mediated <em>Mgp</em> deletion in APCs. ScRNA-seq showed two new adipose-derived stem cells (ASC) populations, ASC1 and ASC4, emerging after <em>Mgp</em> deletion. Trajectory analysis found that ASC1 and ASC4 were derived from ASC2, which normally undergo adipogenesis but instead had diverted to fibrogenic differentiation. All three ASCs expressed <em>Pdgfra</em> and dipeptidyl peptidase-4 (<em>Dpp4</em>). Inhibition of TGFβ signaling or DPP4 activity in mice with <em>Pdgfra</em>-Cre-mediated <em>Mgp</em> deletion reduced the size of the PDGFRα+; DPP4+ cell population and rescued the WAT from unwanted fibrosis.</div></div><div><h3>Conclusions</h3><div>MGP is essential for appropriate balance between adipogenic differentiation and fibroblast activation. Dysregulation of PDGFRα+; DPP4+ cells may signal early adipose fibrosis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102231"},"PeriodicalIF":6.6,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804371","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":"A DEL-1/αvβ3 integrin axis promotes brown adipocyte progenitor proliferation and cold-induced brown adipose tissue adaptation","authors":"Kyoung-Jin Chung ,&nbsp;Antonios Chatzigeorgiou ,&nbsp;Jong-Hyung Lim ,&nbsp;Xiaofei Li ,&nbsp;Ismini Marava ,&nbsp;Dong-Young Kim ,&nbsp;Anke Witt ,&nbsp;Janine Gebler ,&nbsp;Sylvia Grossklaus ,&nbsp;Bettina Gercken ,&nbsp;Irakli Kopaliani ,&nbsp;Pallavi Subramanian ,&nbsp;Matthias Blüher ,&nbsp;Khalil Bdeir ,&nbsp;Vasileia Ismini Alexaki ,&nbsp;George Hajishengallis ,&nbsp;Triantafyllos Chavakis","doi":"10.1016/j.molmet.2025.102229","DOIUrl":"10.1016/j.molmet.2025.102229","url":null,"abstract":"<div><h3>Objectives</h3><div>Cold-triggered adaptation of the brown adipose tissue (BAT) promotes increased non-shivering thermogenesis and helps maintain body temperature. This study investigated the role of the secreted protein developmental endothelial locus-1 (DEL-1) in regulating BAT adaptation to cold.</div></div><div><h3>Methods</h3><div>DEL-1 expression in BAT was assessed following cold exposure in mice. The role of DEL-1 in cold-induced BAT adaptation, thermogenesis and proliferation of brown adipocyte progenitor cells was analyzed by utilizing genetically modified mouse models. Mechanistic insights into DEL-1-mediated regulation of brown adipocyte progenitor proliferation were obtained through in vitro assays.</div></div><div><h3>Results</h3><div>DEL-1 was expressed in the vascular endothelium of the BAT and its expression was upregulated upon cold exposure. By interacting with αvβ3 integrin on brown adipocyte progenitor cells, DEL-1 promoted their proliferation in a manner dependent on AKT signaling and glycolysis activation. Compared to DEL-1-sufficient mice, DEL-1-deficient mice or mice expressing a non-integrin-binding mutant of DEL-1 carrying an Asp-to-Glu substitution in its RGD motif, displayed decreased cold tolerance. This phenotype was associated with impaired BAT adaptation to cold and reduced brown adipocyte progenitor cell proliferation. Conversely, endothelial-specific DEL-1 overexpression in DEL-1-deficient mice restored the BAT thermogenic response to cold.</div></div><div><h3>Conclusions</h3><div>Together, the DEL-1/αvβ3 integrin-dependent endothelial-brown adipocyte progenitor cell crosstalk promotes cold-stimulated BAT adaptation. This knowledge could be potentially harnessed therapeutically for promoting BAT expansion towards improving systemic metabolism.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102229"},"PeriodicalIF":6.6,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775812","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":"Leukocyte-type 12/15-lipoxygenase is essential for timely inflammation-resolution and effective tissue regeneration following skeletal muscle injury","authors":"Binayok Sharma ,&nbsp;Xinyue Lu ,&nbsp;Hamood Rehman ,&nbsp;Vandré C. Figueiredo ,&nbsp;Carol Davis ,&nbsp;Holly Van Remmen ,&nbsp;Shihuan Kuang ,&nbsp;Susan V. Brooks ,&nbsp;Krishna Rao Maddipati ,&nbsp;James F. Markworth","doi":"10.1016/j.molmet.2025.102224","DOIUrl":"10.1016/j.molmet.2025.102224","url":null,"abstract":"<div><h3>Objectives</h3><div>Unlike traditional anti-inflammatory therapies which may interfere with musculoskeletal tissue repair, pharmacological administration of specialized pro-resolving lipid mediators (SPMs) promotes timely resolution of inflammation while stimulating skeletal muscle regeneration. Despite this, the potential role of endogenous inflammation-resolution circuits in skeletal muscle injury and repair remains unknown.</div></div><div><h3>Methods</h3><div>We investigated the effect of whole-body knockout of leukocyte-type 12/15-lipoxygenase (12/15-LOX) on acute inflammation and regeneration <em>in vivo</em> following skeletal muscle injury in mice. We further tested the impact of 12/15-LOX deficiency on polarization of bone marrow-derived macrophages and differentiation of myogenic progenitor cells in vitro.</div></div><div><h3>Results</h3><div><em>Alox15</em>^−/− mice displayed lower intramuscular concentrations of 12/15-LOX-derived lipid mediators than wild type (WT) mice, and this was associated with chronic low-grade muscle inflammation. <em>Alox15-/-</em> mice mounted an exaggerated acute immune response to sterile skeletal muscle injury which was associated with a local imbalance of pro-inflammatory vs. pro-resolving lipid mediators. <em>Alox15</em>^−/− mice also displayed defects in myogenic gene expression, myofiber size, and myonuclear accretion. Mechanistically, bone marrow-derived macrophages (MФ) obtained from <em>Alox15</em>^−/− mice produced less 12/15-LOX-derived lipid mediators and this was associated with impaired M2 polarization. Isolated myogenic progenitor cells also produced many LOX metabolites in response to long chain polyunsaturated fatty acid (LC-PUFA) supplementation, including bioactive SPMs. <em>Alox15</em>^−/− myoblasts were both impaired in their ability to produce SPMs and were insensitive to the stimulatory effect of LC-PUFAs on <em>in vitro</em> myogenesis.</div></div><div><h3>Conclusions</h3><div>12/15-LOX is essential for timely resolution of acute inflammation and direct determination of myogenic progenitor cell fate following skeletal muscle injury.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102224"},"PeriodicalIF":6.6,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794909","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":"Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue","authors":"Ayushi Mittal ,&nbsp;Paul Buscaglia ,&nbsp;Dhiraj Srivastava ,&nbsp;Nikolai O. Artemyev ,&nbsp;Julien A. Sebag","doi":"10.1016/j.molmet.2025.102230","DOIUrl":"10.1016/j.molmet.2025.102230","url":null,"abstract":"<div><h3>Objectives</h3><div>A hallmark of type II diabetes is an impairment of the glucose transporter GLUT4 translocation to the plasma membrane of specialized cells in response to insulin. Identifying mechanisms involved in this defect is critical to developing treatments that restore insulin sensitivity. We previously identified a small molecule insulin sensitizer, C59, which improves insulin-stimulated GLUT4 translocation through binding to Unc119b, however, the role and mechanism of Unc119b-mediated regulation of GLUT4 trafficking is unknown.</div></div><div><h3>Methods</h3><div>Here we use in vitro systems and rodent models of insulin resistance with genetic manipulations of Unc119b expression to uncover the role of this protein in the regulation of glucose homeostasis.</div></div><div><h3>Results</h3><div>We demonstrate that Unc119b is an endogenous inhibitor of GLUT4 translocation which contributes to the development of insulin resistance in obese individuals. We show that Unc119b interacts with Rac1 and inhibits its activation by insulin, resulting in reduced GLUT4 translocation. Both the prenylated C-terminus of Rac1 and C59 bind to the same site within Unc119b, thus suggesting that C59 enhances GLUT4 translocation by interfering with the action of Unc119b on Rac1.</div></div><div><h3>Conclusions</h3><div>Overall, this study identifies Unc119b as a critical regulator of glucose homeostasis, uncovers its role in GLUT4 trafficking, and identifies the mechanism of action of a new class of insulin sensitizers.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102230"},"PeriodicalIF":6.6,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775814","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":"Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue","authors":"Dorota Kaminska ,&nbsp;Calvin Pan ,&nbsp;Laurent Vergnes ,&nbsp;Ashlyn Ro ,&nbsp;Gurugowtham Ulaganathan ,&nbsp;Aldons J. Lusis","doi":"10.1016/j.molmet.2025.102227","DOIUrl":"10.1016/j.molmet.2025.102227","url":null,"abstract":"<div><h3>Objective</h3><div>Sex differences in adipose tissue impact metabolic health, but the underlying molecular mechanisms remain unclear. We previously identified a female-specific chr17 <em>trans</em>-eQTL hotspot regulating mitochondrial gene expression in gonadal white adipose tissue (gWAT). Here, we tested whether iWAT contributes comparably to sex differences in mitochondrial function and futile cycling.</div></div><div><h3>Methods</h3><div>We analyzed iWAT and gWAT from male and female mice across 58 genetically diverse Hybrid Mouse Diversity Panel (HMDP) strains fed a high-fat, high-sucrose diet. We assessed mitochondrial DNA (mtDNA), oxidative phosphorylation (OXPHOS) and futile cycle gene expression, performed genetic mapping, and measured respiration.</div></div><div><h3>Results</h3><div>In gWAT, females showed higher mtDNA, OXPHOS expression, and a female-specific chr17 trans-eQTL, correlating with metabolic traits. In contrast, iWAT lacked this hotspot and showed higher mtDNA, OXPHOS expression, and respiration in males. Lipid cycling genes (<em>Lipe</em>, <em>Mgll</em>, <em>Pnpla2</em>) were elevated in male iWAT, while <em>Mpc1</em>, <em>Mpc2</em>, and <em>Pck1</em> were enriched in female gWAT. <em>Ucp1</em> was higher in female gWAT but not sex-biased in iWAT. <em>Alpl</em> (TNAP), key creatine cycling gene, was upregulated in females in both depots, particularly in iWAT.</div></div><div><h3>Conclusions</h3><div>Female gWAT shows genetically driven mitochondrial regulation linked to metabolic protection, whereas male iWAT has higher mitochondrial content, OXPHOS expression, and respiration. Elevated lipolytic enzymes in male iWAT suggest greater FFA release, while higher pyruvate import and glyceroneogenesis genes in female gWAT favor FFA recycling. <em>Alpl</em> upregulation in females indicates sex-biased UCP1-independent thermogenesis. These depot- and sex-specific signatures reflect distinct metabolic strategies and highlight the need to consider both in adipose research.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102227"},"PeriodicalIF":6.6,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775813","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":"Effects of β-catenin deficiency on adipose tissue physiology","authors":"Romina M. Uranga ,&nbsp;Akira Nishii ,&nbsp;Jessica N. Maung ,&nbsp;Hiroyuki Mori ,&nbsp;Brian Desrosiers ,&nbsp;Jannis Jacobs ,&nbsp;Keegan S. Hoose ,&nbsp;Rebecca L. Schill ,&nbsp;Devika P. Bagchi ,&nbsp;Hannah Guak ,&nbsp;Clair Crewe ,&nbsp;Ivo D. Dinov ,&nbsp;Erin D. Giles ,&nbsp;Carey N. Lumeng ,&nbsp;Ormond A. MacDougald","doi":"10.1016/j.molmet.2025.102226","DOIUrl":"10.1016/j.molmet.2025.102226","url":null,"abstract":"<div><h3>Objectives</h3><div>Compelling evidence from investigation of preclinical models and humans links canonical Wnt/β-catenin signaling to regulation of many aspects of white adipose tissue development and physiology. Dysregulation of this ancient pathway alters adiposity and metabolic homeostasis. Herein we explore how disruption of adipocyte Wnt/β-catenin signaling affects gene expression and crosstalk between cell types within adipose tissue.</div></div><div><h3>Methods</h3><div>To investigate mechanisms through which adipose tissue attempts to maintain homeostasis in the absence of β-catenin in adipocytes, we employed standard methods of metabolic phenotyping as well as bulk RNA sequencing, flow cytometry, single-cell RNA sequencing, and isolation of secreted extracellular vesicles.</div></div><div><h3>Results</h3><div>Our experiments reveal that male, but not female adipocyte-specific β-catenin knockout mice, <em>Ctnnb1</em>^{<em>AdKO</em>}, have an increase in adiposity and insulin resistance. Whereas metabolic processes including fatty acid metabolism were suppressed in adipocytes, mitochondrial metabolism of immune cells was made more efficient, resulting in reduced reactive oxygen species in macrophages and dendritic cells. Deficiency of β-catenin in adipocytes altered the transcriptome of numerous stromal-vascular cell populations including adipose stem and progenitor cells, macrophages, and other immune cells. Homeostasis in white adipose tissue of <em>Ctnnb1</em>^{<em>AdKO</em>} mice is maintained in part by elevated expression of <em>Ctnnb1</em> mRNA in endothelial cells and in secreted small extracellular vesicles.</div></div><div><h3>Conclusions</h3><div>Our studies demonstrate the importance of adipocyte Wnt signaling for regulation of lipid and mitochondrial metabolic processes in stromal-vascular cells and adipocytes in adipose tissues. This research provides further support for an intercellular Wnt signaling network with compensatory capability to maintain homeostasis, and underscores importance of Wnt/β-catenin signaling for understanding adipose tissue physiology and pathophysiology.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102226"},"PeriodicalIF":6.6,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784852","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 brainstem BBSome regulates glucose homeostasis and lean mass in a state-dependent manner","authors":"Connor Laule ,&nbsp;Deng-Fu Guo ,&nbsp;Yuying Zhao ,&nbsp;Paul A. Williams ,&nbsp;Donald A. Morgan ,&nbsp;Younes Rouabhi ,&nbsp;Miriam McDonough ,&nbsp;Trevor Butler ,&nbsp;Jon Resch ,&nbsp;Kamal Rahmouni","doi":"10.1016/j.molmet.2025.102222","DOIUrl":"10.1016/j.molmet.2025.102222","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity disrupts metabolic homeostasis through changes in brain function. Hypothalamic cilia and associated proteins, such as the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins, have been implicated in metabolic regulation and disorders. Here, we investigated the significance of brainstem cilia and the BBSome for energy balance and glucose homeostasis.</div></div><div><h3>Methods</h3><div>Primary cilia were assessed by immunofluorescence and confocal imaging, and brainstem neuron transcriptomes were analyzed using single-cell RNA sequencing. Mice with Phox2b-specific deletion of <em>Ift88</em> or <em>Bbs1</em> were studied under control or high-fat diets. Metabolic tests, insulin signaling, nerve recordings, and viral techniques were used to evaluate the impact of cilia or <em>Bbs1</em> disruption.</div></div><div><h3>Results</h3><div>We found that diet-induced obese mice display increased primary cilia length in the nucleus tractus solitarius. Single cell RNAseq revealed that cilia related genes are enriched in glutamatergic dorsal vagal complex (DVC) neurons expressing <em>Phox2b.</em> Primary cilia deletion in Phox2b neurons (Phox2b^Cre/Ift88 ^fl/fl) caused a mild weight reduction during adolescence without altering metabolic homeostasis during adulthood. We next investigated the brainstem BBSome using Phox2b^Cre/Bbs1^fl/fl mice, which exhibited reduced adolescent lean mass gain but normal adult body weight. Surprisingly, these mice developed glucose intolerance and elevated fasting glucose associated with contrasting changes in hepatic sympathetic and parasympathetic activity, pointing to autonomic imbalance as a cause of glucose dysregulation. Targeted BBSome disruption in the DVC replicated elevations in fasting glucose and chemogenetic DVC Phox2b neuron activation attenuated hyperglycemia during glucose tolerance test and suppressed hepatic sympathetic nerve activity. Interestingly, diet-induced obese Phox2b^Cre/Bbs1^fl/fl mice exhibited lower lean mass and a paradoxical improvement in glucose tolerance despite insulin resistance, suggesting a complex role for the brainstem BBSome in obesity-associated metabolic dysfunction.</div></div><div><h3>Conclusions</h3><div>Our findings highlight novel brainstem mechanisms regulating metabolic homeostasis and distinct roles for primary cilia and the BBSome in glucose regulation and lean mass.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102222"},"PeriodicalIF":6.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760571","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":"Inhibition of pyrimidine de novo synthesis fosters Treg cells and reduces diabetes development in models of Type 1 Diabetes","authors":"Hannah Hipp ,&nbsp;Camilla Tondello ,&nbsp;Hanna Gmehling ,&nbsp;Lena K. Scholz ,&nbsp;Antigoni Stavridou ,&nbsp;Maike Becker ,&nbsp;Anne-Marie Bührer ,&nbsp;Edith Hintermann ,&nbsp;Sandra M. Dirschl ,&nbsp;Till M. Johannsmann ,&nbsp;Martin G. Scherm ,&nbsp;Hella Kohlhof ,&nbsp;Isabelle Serr ,&nbsp;Urs Christen ,&nbsp;Carolin Daniel","doi":"10.1016/j.molmet.2025.102218","DOIUrl":"10.1016/j.molmet.2025.102218","url":null,"abstract":"<div><h3>Objective</h3><div>In autoimmune Type 1 Diabetes (T1D), aberrant immune activation promotes regulatory T cell (Treg) impairments thereby boosting progression of islet autoimmunity. Consequently, there is a progressive destruction of the insulin-producing beta cells in the pancreas. Controlling overshooting immune activation represents a relevant approach to allow for efficient Treg-targeting by broadening the window of opportunity to induce Tregs.</div></div><div><h3>Methods</h3><div>We investigated the effect of restricting pyrimidine <em>de novo</em> synthesis during islet autoimmunity and T1D by Dihydroorotate dehydrogenase (DHODH) inhibition using the next-generation DHODH inhibitor Vidofludimus calcium. We assessed Treg-inducing features of DHODH inhibition in T cells from ongoing murine islet autoimmunity and human T1D <em>in vitro</em>. To dissect the functional relevance of these observations, we tested the impact of DHODH inhibition on interfering with autoimmune activation and disease progression in pre-clinical models of T1D <em>in vivo</em>.</div></div><div><h3>Results</h3><div>We show that DHODH inhibition results in enhanced Treg induction <em>in vitro</em> especially during increased immune activation and reduced T cell proliferation. In addition, Vidofludimus calcium reduced T1D incidence in two mouse models. On the cellular level, treated mice showed reduced T cell activation accompanied by increased Treg frequencies.</div></div><div><h3>Conclusions</h3><div>We demonstrate that restricting pyrimidine <em>de novo</em> synthesis by next-generation DHODH inhibition is a strategy to interfere with autoimmune activation while fostering Tregs.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102218"},"PeriodicalIF":6.6,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708182","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":"Exercise training remodels inter-organ endocrine networks","authors":"Cheehoon Ahn ,&nbsp;Andrea L. Hevener ,&nbsp;Laurie J. Goodyear ,&nbsp;Sue C. Bodine ,&nbsp;Karyn A. Esser ,&nbsp;Marcus M. Seldin ,&nbsp;Lauren M. Sparks","doi":"10.1016/j.molmet.2025.102219","DOIUrl":"10.1016/j.molmet.2025.102219","url":null,"abstract":"<div><h3>Background</h3><div>Exercise induces organism-wide molecular adaptations, partly mediated by humoral factors released in response to acute and chronic physical activity. However, the extent and specificity of endocrine effects from training-induced secreted factors remain unclear.</div></div><div><h3>Methods</h3><div>Here, we applied systems genetics approaches to quantify inter-organ endocrine networks using multi-tissue transcriptomics and proteomics data collected from endurance-trained rats in The Molecular Transducers of Physical Activity Consortium (MoTrPAC).</div></div><div><h3>Results</h3><div>Eight weeks of endurance training significantly altered both the magnitude and specificity of endocrine effects across multiple origin-target tissue pairs. Subcutaneous white adipose tissue emerged as a key endocrine regulator impacted by training, while extracellular matrix-derived factors were identified as globally regulated secretory features in trained vs sedentary animals. Notably, secretory Wnt signaling factors were identified as key mediators of exercise-induced endocrine adaptations in multiple tissues.</div></div><div><h3>Conclusion</h3><div>Our systems genetics framework provides an unprecedented atlas of inter-organ communication significantly remodeled by endurance exercise, serving as a valuable resource for novel exerkine discovery.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102219"},"PeriodicalIF":6.6,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699041","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":"Control of physiologic glucose homeostasis via hypothalamic modulation of gluconeogenic substrate availability","authors":"Jiaao Su ,&nbsp;Abdullah Hashsham ,&nbsp;Nandan Kodur ,&nbsp;Carla Burton ,&nbsp;Amanda Mancuso ,&nbsp;Anjan Singer ,&nbsp;Jennifer Wloszek ,&nbsp;Abigail J. Tomlinson ,&nbsp;Warren T. Yacawych ,&nbsp;Jonathan N. Flak ,&nbsp;Kenneth T. Lewis ,&nbsp;Lily R. Oles ,&nbsp;Hiroyuki Mori ,&nbsp;Nadejda Bozadjieva-Kramer ,&nbsp;Adina F. Turcu ,&nbsp;Ormond A. MacDougald ,&nbsp;Martin G. Myers ,&nbsp;Alison H. Affinati","doi":"10.1016/j.molmet.2025.102216","DOIUrl":"10.1016/j.molmet.2025.102216","url":null,"abstract":"<div><h3>Objectives</h3><div>The brain mobilizes glucose in emergency situations such as hypoglycemia as well as during day-to-day physiology such as fasting. While most hypothalamic neuronal populations that contribute to glucose mobilization also contribute to other aspects of metabolism, neurons in the ventromedial nucleus of the hypothalamus that express the <em>cholecystokinin b receptor</em> (VMH^Cckbr neurons) support glucose production during hypoglycemia without controlling energy homeostasis. However, their role in day-to-day glucose physiology and the mechanisms they engage to support glucose mobilization is unclear.</div></div><div><h3>Methods</h3><div>We used continuous glucose monitoring in mice with chronically silenced VMH^Cckbr neurons to establish whether these neurons are required during day-to-day glucose homeostasis. Tetanus-toxin based chronic silencing and acute optogenetic activation were followed by analysis of hepatic glucose metabolism and white adipose tissue lipolysis.</div></div><div><h3>Results</h3><div>We found that VMH^Cckbr neurons support glucose homeostasis during short fasts and contribute to gluconeogenic substrate mobilization and lipolysis. VMH^Cckbr neurons mobilize glucose without depleting hepatic glycogen or increasing gluconeogenic gene expression, but instead mobilize glycerol in a β3-adrenergic receptor (β3-AR)-dependent manner. Restoring glycerol availability following VMH^Cckbr neuron silencing restores glucose. Finally, acute activation of VMH^Cckbr neurons mobilizes additional gluconeogenic substrates beyond glycerol.</div></div><div><h3>Conclusions</h3><div>VMH^Cckbr neurons represent a distinct subset of glucose-mobilizing VMH neurons that support physiologic glucose homeostasis, likely through control of β3-AR-mediated gluconeogenic substrate mobilization and lipolysis. The presence of different glucose-mobilizing neuronal populations that engage distinct mechanisms in a context-dependent manner may provide the brain with flexibility to coordinate the appropriate glycemic response to different circumstances.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102216"},"PeriodicalIF":6.6,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675299","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}