Molecular Metabolism最新文献

{"title":"Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues","authors":"Jonathan D. Douros ,&nbsp;Megan Capozzi ,&nbsp;Aaron Novikoff ,&nbsp;Jacek Mokrosinski ,&nbsp;Barent DuBois ,&nbsp;Joseph Stock ,&nbsp;Rebecca Rohlfs ,&nbsp;Mikayla Anderson ,&nbsp;Dominika J. Jedrzejcyk ,&nbsp;Svend Poulsen ,&nbsp;Erik Oude Blenke ,&nbsp;Tomas Dago ,&nbsp;Kasper Huus ,&nbsp;Peder L. Nørby ,&nbsp;Sune Kobberup ,&nbsp;Marita Rivir ,&nbsp;Joyce Sorrell ,&nbsp;Stephanie A. Mowery ,&nbsp;Daniel J. Drucker ,&nbsp;David A. D'Alessio ,&nbsp;Patrick J. Knerr","doi":"10.1016/j.molmet.2026.102327","DOIUrl":"10.1016/j.molmet.2026.102327","url":null,"abstract":"<div><h3>Objectives</h3><div>Unimolecular triagonists drive substantial weight loss in patients with obesity by engaging the glucagon-like peptide 1 receptor (GLP-1R) and glucose dependent insulinotropic polypeptide receptor (GIPR) to reduce food intake (FI) and the hepatic glucagon receptor (GcgR) to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects, including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R mono-agonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes.</div></div><div><h3>Methods</h3><div>We used an adeno-associated virus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure.</div></div><div><h3>Results</h3><div>Agonism of the ectopic GLP-1R with either semaglutide, a cAMP biased GLP-1R analogue (NNC5840), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to peptide agonist treatment alone.</div></div><div><h3>Conclusions</h3><div>This represents a novel mechanism for achieving poly-pharmacology to treat obesity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102327"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137717","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":"GCGR agonism requires GABAergic signaling in the medial basal hypothalamus to promote weight loss in obese mice","authors":"Andrew J. Elmendorf ,&nbsp;Ellen Conceição Furber ,&nbsp;Betty Lorentz ,&nbsp;Connor A. Mahler ,&nbsp;Brian A. Droz ,&nbsp;Richard Cosgrove ,&nbsp;Jonquil Marie Poret ,&nbsp;Patrick J. Knerr ,&nbsp;Ricardo J. Samms ,&nbsp;Jonathan N. Flak","doi":"10.1016/j.molmet.2026.102328","DOIUrl":"10.1016/j.molmet.2026.102328","url":null,"abstract":"<div><div>Glucagon receptor (GCGR)-mediated thermogenesis is a key component for the next-generation of obesity therapeutics. Herein, we investigated the central and peripheral mechanism by which activation of the GCGR augments metabolic rate to promote weight loss. Chronic treatment of obese mice with a long-acting GCGR agonist (LAGCGRA) reduced body weight and fat mass at both room temperature and thermoneutrality. Metabolic cage studies highlight that whilst GCGR agonism induces a negative energy balance via effects on both sides of energy balance, weight loss is primarily due to augmented metabolic rate in obese mice. Mechanistically, we report for the first time that GCGR agonism recruits GABAergic signaling in the medial basal hypothalamus to promote uncoupling protein 1(UCP1)-dependent thermogenesis in adipose tissue, stimulate caloric expenditure, and drive a negative energy balance in obese mice. Our preclinical findings provide insight in to how multi-receptor agonists engaging the GCGR may function to improve the weight loss efficacy of anorectic agents. Collectively, our results point to a liver→brain→fat axis activated by GCGR agonism for weight loss in obesity. Future studies are required to validate our findings in the clinic.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102328"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137755","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":"ANKRD53 is downregulated in human obesity and coordinates lipolysis with mitochondrial oxidative metabolism in adipocytes","authors":"Yingying Su ,&nbsp;Xiaoya Li ,&nbsp;Yikai Wang ,&nbsp;Xuhong Lu ,&nbsp;Yafen Ye ,&nbsp;Jingjing Sun ,&nbsp;Tianwen Liu ,&nbsp;Jinghao Cai ,&nbsp;Xiaojing Ma ,&nbsp;Ying Yang ,&nbsp;Jian Zhou","doi":"10.1016/j.molmet.2026.102330","DOIUrl":"10.1016/j.molmet.2026.102330","url":null,"abstract":"<div><h3>Aims</h3><div>Human adipose tissue is central to obesity-associated metabolic dysfunction. ANKRD53 is a human-specific, adipocyte-enriched ankyrin repeat scaffold protein with largely unknown function. We investigated its role in human adipocyte metabolism and the underlying mechanism.</div></div><div><h3>Methods</h3><div>RNA-seq analysis of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from 236 individuals quantified <em>ANKRD53</em> expression and its association with metabolic traits. In human primary adipocytes, we assessed lipolysis (free fatty acid and glycerol release) and mitochondrial respiration (oxygen consumption rate) after ANKRD53 overexpression or knockdown. An AAV was used to overexpress ANKRD53 in mouse inguinal white adipose tissue (iWAT). Protein interactors were identified by immunoprecipitation–mass spectrometry, and knockdown experiments confirmed a functional role of ACSL1.</div></div><div><h3>Results</h3><div><em>ANKRD53</em> expression in both adipose depots was markedly reduced in obesity and inversely correlated with BMI, adiposity measures, insulin resistance indices, and circulating triglycerides, while positively associated with adiponectin and HDLc. In human adipocytes, ANKRD53 overexpression enhanced forskolin-stimulated lipolysis and mitochondrial respiration, whereas silencing impaired these processes. Adipose-targeted ANKRD53 overexpression in mice increased lipolysis in vivo. Mechanistically, ANKRD53 interacted with ACSL1 and promoted its mitochondrial localization, channeling lipolysis-derived FFAs into β-oxidation; silencing ACSL1 abrogated ANKRD53's effects.</div></div><div><h3>Conclusions</h3><div>ANKRD53 is reduced in obesity and coordinates lipolysis with mitochondrial oxidative metabolism in human adipocytes, promoting efficient use of lipolysis-derived FFAs via ACSL1. These findings establish ANKRD53 as a key regulator of adipocyte energy metabolism and a potential therapeutic target for improving metabolic health in obesity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102330"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137764","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":"Sodium-glucose cotransporter-specific substrate αMG stimulates endogenous glucagon secretion and ameliorates obesity-associated metabolic disorders in mice","authors":"Takayoshi Suga ,&nbsp;Yoko Tabei ,&nbsp;Osamu Kikuchi ,&nbsp;Daisuke Kohno ,&nbsp;Yuichi Ikeuchi ,&nbsp;Masaki Kobayashi ,&nbsp;Yuko Nakagawa ,&nbsp;Hiroki Tojima ,&nbsp;Yuichi Yamazaki ,&nbsp;Ken Sato ,&nbsp;Satoru Kakizaki ,&nbsp;Takashi Nishimura ,&nbsp;Yoshio Fujitani ,&nbsp;Takumi Takizawa ,&nbsp;Toshio Uraoka ,&nbsp;Tadahiro Kitamura","doi":"10.1016/j.molmet.2026.102324","DOIUrl":"10.1016/j.molmet.2026.102324","url":null,"abstract":"<div><h3>Objectives</h3><div>While glucagon raises blood glucose levels, it also promotes lipolysis and energy expenditure, and suppresses food intake and gastrointestinal motility, thereby resulting in weight loss. We previously reported that sodium-glucose cotransporter 1 (SGLT1) is highly expressed in pancreatic α cells. The present study aimed to investigate the effects of α-methyl <span>d</span>-glucopyranoside (αMG), an SGLT-specific substrate, on endogenous glucagon secretion and metabolic parameters in obese diabetic mice.</div></div><div><h3>Methods</h3><div>We injected αMG intraperitoneally daily into high fat, high sucrose diet (HFHSD)-fed mice and <em>db/db</em> mice, and measured metabolic parameters including plasma glucagon concentration. During the treatment with αMG, we evaluated various metabolic conditions, such as body weight, glucose tolerance and hepatic steatosis, in these mice. We also used SGLT1-specific inhibitor and liver-specific glucagon receptor knockout mice to elucidate the underlying mechanism.</div></div><div><h3>Results</h3><div>We showed that αMG stimulates endogenous glucagon secretion, and that chronic injection of αMG led to dramatic weight loss, improved glucose intolerance, and ameliorated hepatic steatosis, by reducing food intake and increasing energy expenditure and fat utilization, among obese diabetic mice. Interestingly amelioration of hepatic steatosis was abolished in liver-specific glucagon receptor knockout mice, but body weight reduction was not abolished. In addition, αMG, although to a modest extent, distinctly enhanced urinary glucose excretion.</div></div><div><h3>Conclusions</h3><div>These results in this study suggest that αMG stimulates endogenous glucagon secretion and may lead to a therapeutic strategy for obesity-associated metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102324"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097293","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":"Elevated activity of the mesolimbic dopamine system promotes feeding during pregnancy in mice","authors":"Tanya Pattnaik ,&nbsp;Benjamin Wang ,&nbsp;Patrick Sweeney","doi":"10.1016/j.molmet.2026.102323","DOIUrl":"10.1016/j.molmet.2026.102323","url":null,"abstract":"<div><div>The pregnancy period is accompanied by increased feeding behavior to accommodate the elevated energy demands associated with fetal growth and development. However, the underlying neural circuitry and molecular mechanisms mediating increased feeding during pregnancy are largely unknown. Here, we utilized a combination of fiber photometry, chemogenetics, and mouse behavioral assays to characterize altered feeding behavior during pregnancy in mice. We uncover that pregnancy increases the average activity of the mesolimbic dopamine system during feeding behavior in mice. VTA dopamine neurons promote increased high fat diet feeding during pregnancy as inhibition of these cells selectively reduces acute high fat diet intake in pregnant mice. Further, pregnant mice exhibit increased sensitivity to food deprivation, an effect which requires activity of the mesolimbic dopamine system. Together, these findings provide a circuit basis mediating altered palatable food intake and sensitivity to negative energy balance during pregnancy in mice.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102323"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis","authors":"Andres F. Ortega ,&nbsp;Cha Mee Vang ,&nbsp;Ferrol I. Rome ,&nbsp;Kaitlyn M. Andreoni ,&nbsp;Aiden M. Phoebe ,&nbsp;Alisa B. Nelson ,&nbsp;Peter A. Crawford ,&nbsp;James J. Galligan ,&nbsp;Stanley Ching-Cheng Huang ,&nbsp;Curtis C. Hughey","doi":"10.1016/j.molmet.2026.102325","DOIUrl":"10.1016/j.molmet.2026.102325","url":null,"abstract":"<div><div>Dietary sulfur amino acid restriction (SAAR) improves whole-body glucose homeostasis, elevates liver insulin action, and lowers liver triglycerides. These adaptations are associated with an increased expression of hepatic <em>de novo</em> serine synthesis enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). This study tested the hypothesis that enhanced hepatic serine synthesis is necessary for glucose and lipid adaptations to SAAR. Hepatocyte-specific PSAT1 knockout (KO) mice and wild type (WT) littermates were fed a high-fat control or SAAR diet. In WT mice, SAAR increased liver PSAT1 protein (∼70-fold), serine concentration (∼2-fold), and ¹³C-serine (∼20-fold) following an intravenous infusion of [U–¹³C]glucose. The elevated liver serine and partitioning of circulating glucose to liver serine by SAAR were attenuated in KO mice. This was accompanied by a blunted improvement in glucose tolerance in KO mice fed a SAAR diet. Interestingly, SAAR decreased liver lysine lactoylation, a SAA-supported post-translational modification known to inhibit PHGDH enzymatic activity. This suggests dietary SAAR may increase serine synthesis, in part, by lowering lysine lactoylation. Beyond glucose metabolism, dietary SAAR reduced body weight, adiposity, and liver triglycerides similarly in WT and KO mice. Collectively, these results demonstrate that hepatic PSAT1 is necessary for glucose, but not lipid, adaptations to SAAR.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102325"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125854","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":"Semaphorin 7A regulates axon outgrowth in subcutaneous white adipose tissue","authors":"Jake W. Willows ,&nbsp;Lindsey M. Lazor ,&nbsp;Gabriela Wandling ,&nbsp;William Butke ,&nbsp;Fatma Fenesha ,&nbsp;Kara N. Corps ,&nbsp;Sarah B. Peters ,&nbsp;Kristy L. Townsend","doi":"10.1016/j.molmet.2026.102329","DOIUrl":"10.1016/j.molmet.2026.102329","url":null,"abstract":"<div><h3>Purpose</h3><div>Adipose tissue innervation is critical for regulating lipolysis, adipogenesis, and thermogenesis, yet the mechanisms that establish and maintain these neural networks remain poorly understood. Semaphorin 7A (Sema7A) is a well-characterized axon guidance and neuroimmune signaling molecule that is highly expressed in adipose tissue. Sema7A regulates adipocyte metabolic processes, including lipid accumulation and thermogenic gene expression, via Integrin β1 signaling. However, its potential role in shaping adipose tissue innervation and coordinating neural–metabolic communication has not been explored.</div></div><div><h3>Methods</h3><div>In this study, we investigated a knockout of Sema7A in mice, and its influences on adipose tissue innervation and metabolic regulation during postnatal development and in adulthood, both under baseline conditions and following cold exposure, a potent activator of sympathetic nerve activity and axonal remodeling in scWAT.</div></div><div><h3>Results</h3><div>Deletion of Sema7A increased adiposity at postnatal day 21, marked by enlarged subcutaneous and brown adipose depots and reduced lipolytic enzyme expression. Tyrosine hydroxylase-expressing (TH⁺), and calcitonin gene-related peptide-expressing (CGRP⁺) innervation was markedly reduced, indicating dysregulated neuro-adipose communication. Plexin C1, a receptor for Sema7A, was strongly expressed on subcutaneous adipose axons, suggesting direct signaling to support neuronal growth. In adulthood, Sema7A-deficient mice displayed normal metabolic responses to cold exposure but failed to mount the typical increase in sympathetic axon outgrowth within beige regions of scWAT.</div></div><div><h3>Conclusions</h3><div>Together, these findings identify Sema7A as a critical mediator of adipose neural development and remodeling, required for establishing and maintaining proper innervation and metabolic function.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102329"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137814","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 cell transcriptomics of human weight loss links adipocyte NPY1R to control of lipolysis","authors":"Julius E.R. Grothen ,&nbsp;Jaime M. Martinez ,&nbsp;Nikos Sidiropoulos ,&nbsp;Lucas Massier ,&nbsp;Danae Zareifi ,&nbsp;Jiawei Zhong ,&nbsp;Ida Davidsen ,&nbsp;Jette W. Platou ,&nbsp;Jette Mandelbaum ,&nbsp;Pia Rothe ,&nbsp;Henning Hvid ,&nbsp;Mads Grønborg ,&nbsp;Christian Toft Madsen ,&nbsp;Jens M. Bruun ,&nbsp;Mikael Rydén ,&nbsp;Niklas Mejhert ,&nbsp;Jørn W. Helge ,&nbsp;Zachary Gerhart-Hines ,&nbsp;Thomas Å. Pedersen","doi":"10.1016/j.molmet.2025.102305","DOIUrl":"10.1016/j.molmet.2025.102305","url":null,"abstract":"<div><h3>Background</h3><div>Combination of increased physical exercise and hypocaloric diet has long been recognized to improve cardiometabolic health and adipose tissue function, including lipid turnover. How such lifestyle interventions mediate benefits at the cellular level remains unknown. Given the critical role of subcutaneous white adipose tissue (scWAT) to systemic metabolic homeostasis, we set out to interrogate how exercise and diet lifestyle intervention impacted scWAT in individuals living with obesity, with a particular focus on lipolytic capacity and cell-specific gene profiling.</div></div><div><h3>Methods</h3><div>Single nuclei RNA sequencing (snRNAseq) was performed on cryopreserved scWAT biopsies originally collected before and after lifestyle intervention, involving regular exercise and hypocaloric diet in obese individuals. Findings on regulation of lipolysis in adipocytes were followed up with meta-analysis of clinical studies and pharmacological experiments in mature human adipocytes.</div></div><div><h3>Results</h3><div>snRNAseq analysis revealed intervention-induced changes in all scWAT cell-types. In adipocytes genes linked to protein and organelle turnover, branch chain amino acid catabolism, and lipolytic control were most significantly regulated. We identified a cell autonomous brake on adipocyte lipolysis via the neuropeptide Y receptor 1 (NPY1R). Expression of adipocyte <em>NPY1R</em> was reduced after weight loss and correlated positively with body fat percentage and body mass index. Findings were confirmed in meta-analysis across 23 studies. Finally, we found a negative correlation between <em>NPY1R</em> and beta-adrenergic-induced lipolysis and that NPY dose-dependently attenuated lipolysis and cAMP-signaling in primary human subcutaneous adipocytes.</div></div><div><h3>Conclusions</h3><div>Our work suggests that decreases in adipocyte <em>NPY1R</em> during weight loss boost lipolytic capacity and contribute to improved systemic cardiometabolic health.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102305"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781569","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":"Survodutide acts through circumventricular organs in the brain and activates neuronal regions associated with appetite regulation","authors":"Tina Zimmermann ,&nbsp;Katherin Bleymehl ,&nbsp;Peter Haebel ,&nbsp;Johanna Perens ,&nbsp;Urmas Roostalu ,&nbsp;Jacob Hecksher-Sørensen ,&nbsp;Jonas Doerr ,&nbsp;Sebastian Jarosch ,&nbsp;Daniel Lam ,&nbsp;Holger Klein ,&nbsp;Anton Pekcec ,&nbsp;Samar N. Chehimi ,&nbsp;Richard C. Crist ,&nbsp;Benjamin C. Reiner ,&nbsp;Matthew R. Hayes ,&nbsp;Robert Augustin","doi":"10.1016/j.molmet.2026.102326","DOIUrl":"10.1016/j.molmet.2026.102326","url":null,"abstract":"<div><div>Survodutide is a novel GCG/GLP-1 receptor (GCGR/GLP-1R) dual agonist in clinical development for people with obesity and people with metabolic dysfunction-associated steatohepatitis (MASH). Preclinically, survodutide demonstrated body weight lowering efficacy through decreased energy intake and increased energy expenditure. Here, we investigated the central site of action of survodutide and provide further insights into its mechanism of action in reducing body weight. We assessed <em>GCGR</em> and <em>GLP1R</em> expression in human and mouse circumventricular organs (CVOS) and showed for the first time that <em>GCGR</em> is barely detectable in area postrema (AP) and arcuate nucleus of the hypothalamus (ARH) at the single cell level. In contrast, <em>GLP1R</em> is expressed in these tissues. Using a fluorophore labeled survodutide to visualize sites of action in the mouse brain, survodutide was observed to directly access the CVOs and adjacent hypothalamic and hindbrain nuclei, without evidence of uniformly crossing the blood–brain-barrier. In addition, c-Fos labeling showed that multiple nuclei associated with the control of food intake were activated by survodutide. Consistent with the hypothesis that the intake suppressive effects of survodutide are GLP-1R dependent, a long-acting GCGR agonist did not induce neuronal activation in satiety-mediating regions, nor reduced food intake but showed reduction in body weight. These data further support the dual mode of action of survodutide and its potential to provide clinical benefit for people with obesity and/or MASH.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102326"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119417","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":"α-Parvin promotes glucose uptake and metabolism in skeletal muscle with minimal influence on hepatic insulin sensitivity","authors":"Fabian Bock ,&nbsp;Xinyu Dong ,&nbsp;Kakali Ghoshal ,&nbsp;David A. Cappel ,&nbsp;John W. Deaver ,&nbsp;Dan S. Lark ,&nbsp;Luciano Cozzani ,&nbsp;Deanna P. Bracy ,&nbsp;Louise Lantier ,&nbsp;Allison Do ,&nbsp;Richard L. Printz ,&nbsp;Santosh Thapa ,&nbsp;Owen P. McGuinness ,&nbsp;David H. Wasserman ,&nbsp;Ambra Pozzi ,&nbsp;Roy Zent ,&nbsp;Nathan C. Winn","doi":"10.1016/j.molmet.2026.102322","DOIUrl":"10.1016/j.molmet.2026.102322","url":null,"abstract":"<div><div>Skeletal muscle and liver insulin resistance are early features in the sequelae of type 2 diabetes. Integrins are extracellular matrix receptors expressed on skeletal muscle cells and hepatocytes, which have been implicated in modulating obesity-associated insulin resistance. Integrins regulate cell function through intracellular proteins including the ILK-PINCH-Parvin (IPP) complex. ILK signaling amplifies skeletal muscle and liver insulin resistance in diet-induced obesity in mice but the role of α-Parvin is unexplored. The hyperinsulinemic-euglycemic clamp was used to assess hepatic and muscle insulin action. We demonstrate that deletion of hepatocyte-specific α-Parvin had only minimal influence on obesity-induced liver or whole-body insulin resistance. In contrast, deletion of α-Parvin in skeletal muscle caused a striking reduction in muscle glucose uptake during an insulin clamp in lean mice which was not exacerbated by diet-induced obesity. The decrease in muscle glucose uptake in lean mice was due to a decrease in insulin-mediated GLUT4 membrane recruitment, which was associated with significant morphological abnormalities including actin cytoskeleton dysfunction. In addition, severe muscular dysfunction, blunted mitochondrial oxidative capacity and reduced aerobic exercise capacity were manifest in muscle α-Parvin KO mice. Thus, α-Parvin has a minor role in liver insulin action but is required for insulin-stimulated glucose uptake in skeletal muscle in lean mice due to its role in actin cytoskeleton regulation. These data suggest that individual IPP complex proteins link cell structure to metabolism via distinct mechanisms in a tissue-specific fashion.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102322"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041281","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}