Molecular Metabolism最新文献

{"title":"Spatially diffuse cAMP signalling with oppositely biased GLP-1 receptor agonists in β-cells despite differences in receptor localisation","authors":"Shiqian Chen ,&nbsp;Carolina B. Lobato ,&nbsp;Carissa Wong ,&nbsp;Yusman Manchanda ,&nbsp;Katrina Viloria ,&nbsp;Iona Davies ,&nbsp;Daniel B. Andersen ,&nbsp;Julia Ast ,&nbsp;Kyle W. Sloop ,&nbsp;David J. Hodson ,&nbsp;Johannes Broichhagen ,&nbsp;Steve Bloom ,&nbsp;Jens J. Holst ,&nbsp;Tricia Tan ,&nbsp;Alejandra Tomas ,&nbsp;Ben Jones","doi":"10.1016/j.molmet.2025.102304","DOIUrl":"10.1016/j.molmet.2025.102304","url":null,"abstract":"<div><div>Internalisation of G protein-coupled receptors (GPCRs) can contribute to altered cellular responses by directing signalling from non-canonical locations, such as endosomes. If signalling processes are locally constrained, active receptors in different subcellular locations could produce different downstream effects. This phenomenon may be relevant to the optimal targeting of the glucagon-like peptide-1 receptor (GLP-1R), a type 2 diabetes and obesity target GPCR for which several ligands with varying internalisation tendency have been discovered. To investigate, we compared the signalling localisation effects of two prototypical GLP-1RAs with opposite signal bias and effects on GLP-1R trafficking: exendin-asp3 (ExD3), a full agonist that drives rapid internalisation, and exendin-phe1 (ExF1), which shows much slower internalisation. After using bioorthogonal labelling and fluorescent agonist conjugates to verify the divergent trafficking patterns of ExF1 and ExD3 in β-cell lines and primary pancreatic islets, we used live cell biosensors to monitor signalling at different subcellular locations. This revealed that cAMP/PKA/ERK signalling in β-cells is in fact distributed widely across the cell over short- (&lt;5 min) and medium-term (up to 60 min) stimulation at pharmacological (&gt;10 pM) concentrations, with no major differences in signal localisation that could be linked to internalised <em>versus</em> cell surface-bound GLP-1R. Moreover, washout experiments highlighted that, whilst fast-internalising ExD3 shows much greater accumulation and binding to GLP-1R in endosomes than slow-internalising ExF1, it is a rather inefficient driver of both cAMP production in β-cells and insulin secretion from perfused rat pancreata. These data provide a greater understanding of the cellular effects of biased GLP-1R agonism.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102304"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757158","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":"Additive effects of GLY-200 (oral pharmacologic duodenal exclusion therapy) and GLP-1R agonist in obesity management","authors":"Taylor L. Carlson ,&nbsp;Mark Fineman ,&nbsp;Stace Kernodle ,&nbsp;Chelsea R. Hutch ,&nbsp;Christine Bryant ,&nbsp;Kevin Colbert ,&nbsp;Randy J. Seeley ,&nbsp;Ashish Nimgaonkar","doi":"10.1016/j.molmet.2025.102287","DOIUrl":"10.1016/j.molmet.2025.102287","url":null,"abstract":"<div><div>Type 2 diabetes and obesity impact billions of people and the global prevalence is only growing. Current treatment options, which include pharmacotherapy, e.g., GLP-1 receptor agonists (GLP-1RA) and bariatric surgical approaches have limitations. GLY-200 is an investigational clinical-stage oral non-absorbed polymeric drug designed to target proximal intestinal mucin and enhance its barrier function, emulating duodenal exclusion physiology for the treatment of diabetes and obesity. The efficacy of GLY-200 as a monotherapy and in combination with semaglutide, a leading GLP-1 receptor agonist (GLP-1RA) for obesity weight management was evaluated in diet-induced obesity (DIO) mice. Significant improvements in metabolic parameters were seen in mice treated with GLY-200 monotherapy. Moreover, an additive effect was observed when GLY-200 was combined with semaglutide, resulting in enhanced weight loss and metabolic improvements beyond those achieved with either treatment alone. GLY-200 showed promise as a weight maintenance drug, significantly blunting the weight rebound seen after GLP-1RA discontinuation. Phase 2a data from patients with type 2 diabetes (T2D) showed reductions in fasting and postprandial blood glucose, improved fasting lipid profiles, and progressive weight loss with GLY-200 treatment. These findings suggest that GLY-200, in combination with GLP-1RAs, holds promise as a novel therapeutic strategy for obesity, potentially offering a valuable approach for GLP-1RA dose reduction or weight maintenance following GLP-1RA discontinuation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102287"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573932","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":"Pancreatic amylin dynamically reconfigures distributed brain networks governing appetite regulation in mice","authors":"Irmak Gezginer ,&nbsp;Giulia Mazzini ,&nbsp;Christelle Le Foll ,&nbsp;Diana Kindler ,&nbsp;Thomas A. Lutz ,&nbsp;Daniel Razansky","doi":"10.1016/j.molmet.2025.102313","DOIUrl":"10.1016/j.molmet.2025.102313","url":null,"abstract":"<div><div>Obesity remains a major global health challenge, yet the brain-wide effects of hormones regulating appetite remain incompletely understood. Amylin, co-secreted with insulin by pancreatic β-cells, promotes satiation and is a promising therapeutic target for metabolic disorders. While its receptor distribution is well-characterized, its influence on large-scale neural dynamics is unknown. Here, resting-state fMRI was used to map time-resolved connectivity changes following peripheral amylin administration in wild-type (WT) and receptor activity-modifying protein 1/3 knockout (RAMP1/3 KO) mice. In WT animals, amylin triggered rapid and transient network reconfigurations, engaging canonical satiation hubs such as the area postrema and parabrachial nucleus, and extending to sensory-integrative areas including the inferior colliculus and insular cortex. Early hindbrain responses propagated to hypothalamic, thalamic, and mesolimbic circuits implicated in appetite and reward. These effects, along with amylin-driven modulation of large-scale networks and low-frequency oscillations, were absent in KO mice. The findings position amylin as a potent modulator of distributed brain circuits, offering a framework for targeted obesity treatments.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102313"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827245","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":"Interaction between time-of-day and oxytocin efficacy in mice and humans with and without gestational diabetes","authors":"Thu Van-Quynh Duong ,&nbsp;Alexandra M. Yaw ,&nbsp;Guoli Zhou ,&nbsp;Niharika Sinha ,&nbsp;Aneesh Sai Cherukuri ,&nbsp;Duong Nguyen ,&nbsp;Kylie Cataldo ,&nbsp;Nicollette Ly ,&nbsp;Aritro Sen ,&nbsp;Lorenzo F. Sempere ,&nbsp;Cara Detrie ,&nbsp;Robert Seiler ,&nbsp;I. Nicholas Olomu ,&nbsp;Rene Cortese ,&nbsp;Robert Long ,&nbsp;Hanne M. Hoffmann","doi":"10.1016/j.molmet.2025.102269","DOIUrl":"10.1016/j.molmet.2025.102269","url":null,"abstract":"<div><div>Due to significant risks of peripartum complications, pregnancies complicated by diabetes often require labor induction or augmentation with synthetic oxytocin. However, the efficacy of oxytocin is often compromised in diabetic pregnancies. Given that diabetes deregulates the body's circadian timekeeping system, our objective was to determine how time of day and the circadian clock gene, <em>Bmal1</em>, gate oxytocin efficacy. We compared oxytocin uterotonic efficacy in a smooth muscle-<em>Bmal1</em> conditional knockout mouse (cKO), and a mouse model of food-induced gestational diabetes. We found that in wild-type mice, the oxytocin receptor is expressed in a time-of-day-dependent manner and is under the control of BMAL1. Both <em>Bmal1</em> cKO and food-induced gestational diabetes mice, which presented with a downregulation of <em>Bmal1</em> in the uterus, had decreased uterine contractility in response to oxytocin. To establish the translational value of these findings, we utilized an immortalized term human myometrial cell line. We determined that the time-of-day impacted oxytocin-induced myometrial contractility <em>in vitro</em>. Furthermore, we conducted a retrospective medical record analysis of 2,367 pregnant patients ≥39 weeks gestation undergoing induction of labor. We assessed the timing of labor induction and the impact of gestational diabetes mellitus on labor duration. Induction of labor in the morning compared to midnight was associated with a ∼1.5-hour and ∼7-hour shorter labor duration in controls and patients with gestational diabetes mellitus, respectively. In conclusion, circadian timing plays a key role in induction of labor and oxytocin responsiveness and should be considered when managing labor induction.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102269"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318456","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":"Nutritional regulation of metabolism-dependent and-independent glucosensing in the mammalian taste system","authors":"Lilly Mai ,&nbsp;Aracely Simental Ramos ,&nbsp;A-Hyun Jung ,&nbsp;Devin de Monteiro ,&nbsp;Isabelle Vu ,&nbsp;Tricia Saputera ,&nbsp;Jonathan Fan ,&nbsp;Tatiyana Adkins ,&nbsp;DeHaven Dickerson ,&nbsp;David W. Pittman ,&nbsp;Sandrine Chometton ,&nbsp;Lindsey A. Schier","doi":"10.1016/j.molmet.2025.102280","DOIUrl":"10.1016/j.molmet.2025.102280","url":null,"abstract":"<div><div>Dietary glucose is a preferred source of energy, but it remains unknown how the mammalian brain rapidly detects and discriminates this sugar from other sweeteners, and whether this depends on nutritional environment and metabolic need. Our results show that signals generated by metabolism-dependent and -independent actions of oral glucose can each be recruited to guide nutrient choice. Further, glucose (or its non-metabolizable analog) evokes a discernible pattern of neural activity from calorie-matched fructose in the central gustatory system, and this is conditioned by diet. Although the brain responses and corresponding consummatory behaviors do not require sweet taste receptor input, the results indicate that the sweet receptor is important for integrating nutritional states with metabolic pathways in the taste system and ultimately guiding intake towards glucose-yielding substrates.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102280"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513350","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 innate thermogenic capacity of brown adipose tissue develops independently of sympathetic signaling","authors":"Ethan C. Fein ,&nbsp;Sarmistha Mukherjee ,&nbsp;Joseph A. Baur ,&nbsp;Patrick Seale","doi":"10.1016/j.molmet.2025.102299","DOIUrl":"10.1016/j.molmet.2025.102299","url":null,"abstract":"<div><div>Brown adipose tissue (BAT) dissipates energy as heat in response to β-adrenergic signaling induced by the sympathetic nervous system (SNS). While this pathway is essential for the cold-induced remodeling and metabolic activity of BAT, its role in developmental programming is unclear. Here, we show that brown adipocytes acquire thermogenic identity during embryogenesis independently of sympathetic innervation and β-adrenergic signaling. Genetic sympathectomy or disrupted β-adrenergic signaling had minimal effects on thermogenic gene expression or tissue morphology during either embryonic or postnatal BAT development in the absence of cold stress. Functional analyses revealed that the SNS is likely required for circulatory support of BAT activity during β-adrenergic stimulation but not for the development of the thermogenic capacity of BAT itself. These findings demonstrate that developmental and cold-responsive BAT remodeling are mechanistically distinct processes. Defining the molecular programs that drive BAT development may reveal new strategies to enhance BAT formation and function without relying on β-adrenergic stimulation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102299"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743408","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":"Beta cell secreted GABA sets appropriate insulin secretion by modulating islet calcium oscillations","authors":"Sandra M. Ferreira ,&nbsp;D. Walker Hagan ,&nbsp;Austin E. Stis ,&nbsp;Adrienne E. Widener ,&nbsp;Alexandra E. Cuaycal ,&nbsp;Chad Rancourt ,&nbsp;Arabella G. Readey ,&nbsp;Dylan S. Smurlick ,&nbsp;Dongtao A. Fu ,&nbsp;Martha Campbell–Thompson ,&nbsp;Marjan Slak Rupnik ,&nbsp;Edward A. Phelps","doi":"10.1016/j.molmet.2025.102268","DOIUrl":"10.1016/j.molmet.2025.102268","url":null,"abstract":"<div><h3>Objectives</h3><div>Gamma-aminobutyric acid (GABA) is produced in pancreatic beta cells and is implicated in modulating islet function, yet its precise physiological role remains uncertain. This study aimed to determine the function of endogenous beta cell-derived GABA on insulin secretion and islet calcium dynamics by developing a conditional beta cell-specific knockout of GABA-synthesizing enzymes (GAD65 and GAD67).</div></div><div><h3>Methods</h3><div>Conditional knockout mice (<em>Gad</em> ^βKO) lacking both GAD65 and GAD67 specifically in pancreatic beta cells were generated. Glucose-stimulated insulin secretion was measured in isolated islets and <em>in vivo</em> and islet Ca²⁺ oscillations were recorded using calcium imaging. The effects of GABA and its receptor agonists/antagonists were tested under various glucose conditions. Additional analyses were performed in high-fat diet-fed mice and human islets from donors with and without type 2 diabetes (T2D).</div></div><div><h3>Results</h3><div><em>Gad</em> ^βKO islets were devoid of GABA and showed excessive insulin secretion in response to glucose without anatomical changes in islet composition. These islets had defective Ca²⁺ oscillations, with prolonged active phases and reduced amplitudes. GABA application suppressed Ca²⁺ oscillations, an effect mediated by GABA_A and GABA_B receptors. High-fat diet-fed and T2D human islets were unresponsive to GABA and exhibited impaired Ca²⁺ oscillations.</div></div><div><h3>Conclusions</h3><div>This is the first study using a beta cell-specific GAD65/GAD67 knockout model. Endogenous beta cell-derived GABA is critical for modulating insulin secretion by maintaining proper Ca²⁺ oscillation dynamics. GABA signaling likely operates as a delayed negative feedback mechanism that reinforces oscillatory homeostasis in islets. The loss of GABA responsiveness, as seen in metabolic stress or T2D, may contribute to islet dysfunction. This work establishes GABA as a key regulator of islet rhythm and glucose responsiveness.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102268"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313216","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":"Isotype-selective roles of hepatic acetyl-CoA carboxylases in a mouse model of fatty liver disease","authors":"Martina Beretta ,&nbsp;Calum S. Vancuylenburg ,&nbsp;Riya Shrestha ,&nbsp;Ellen M. Olzomer ,&nbsp;Brenna Osborne ,&nbsp;Mingyan Zhou ,&nbsp;Suri Zhang ,&nbsp;Adam Hargreaves ,&nbsp;Frances L. Byrne ,&nbsp;Kyle L. Hoehn","doi":"10.1016/j.molmet.2025.102264","DOIUrl":"10.1016/j.molmet.2025.102264","url":null,"abstract":"<div><h3>Objectives</h3><div>Acetyl-CoA carboxylase enzymes ACC1 and ACC2 promote liver fat storage. Accordingly, ACC inhibition represents a strategy to reverse fatty liver disease and related disorders. Human and rodent studies show that targeting both ACC isotypes can reverse some fatty liver phenotypes, but also result in unwanted metabolic phenotypes including hypertriglyceridemia. The objective of this study was to determine whether liver-selective genetic inhibition of ACC1 or ACC2 individually can reverse fatty liver disease phenotypes without adverse metabolic phenotypes in a mouse model of fatty liver disease.</div></div><div><h3>Methods</h3><div>Four genotypes of male C57BL/6J mice floxed for ACC1, ACC2, both ACC alleles, or no ACC alleles were fed an Amylin diet for 28 weeks to induce fatty liver disease. After 20 weeks of Amylin feeding, ACC genes were deleted in the liver by adeno-associated virus 8 (AAV8)-mediated Cre recombinase expression. Mice were metabolically phenotyped and liver disease was assessed by histopathology.</div></div><div><h3>Results</h3><div>Dual inhibition of ACC enzymes was necessary to achieve significant reversal of fatty liver disease and fibrosis; however, it also caused hypertriglyceridemia, weight gain, and glucose intolerance. ACC1 inhibition alone resulted in partial reversal of fatty liver disease phenotypes but drove all undesired metabolic phenotypes. In contrast, ACC2 inhibition alone had minimal effect on fatty liver, fibrosis, or metabolic phenotypes.</div></div><div><h3>Conclusions</h3><div>Our results indicate that complete inhibition of liver ACC activity is required to resolve fatty liver disease and fibrosis, with ACC1 inhibition being the dominant driver of unwanted metabolic dysregulation. Accordingly, selective inhibition of ACC2 with partial inhibition of ACC1 may represent a refined future approach to reverse fatty liver disease phenotypes while minimizing metabolic dysregulation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102264"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233086","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":"Furin may contribute to proglucagon processing and glucagon-like Peptide-1 production in human alpha cells","authors":"Janyne Koepke,&nbsp;Wentong Long,&nbsp;Amy Barr,&nbsp;Peter E. Light","doi":"10.1016/j.molmet.2025.102259","DOIUrl":"10.1016/j.molmet.2025.102259","url":null,"abstract":"<div><h3>Objectives</h3><div>While glucagon-like peptide-1 (GLP-1) production has been previously documented in human alpha cells, the steps regulating its production and secretion are poorly characterized. We investigated the enzymes implicated in proglucagon processing, characterizing their expression and localization in primary human alpha cells and αTC1/9 cells.</div></div><div><h3>Methods</h3><div>Human alpha cells and αTC1/9 cells were maintained in control conditions or exposed to proinflammatory and Akt-activating stimuli to enhance GLP-1 levels. Proglucagon and convertase enzyme gene expression, protein content, and subcellular localization were evaluated by qPCR, Western Blot, and immunofluorescent microscopy, respectively.</div></div><div><h3>Results</h3><div>Our data suggests that the canonical GLP-1-producing enzyme, Prohormone Convertase 1/3 (PC1/3), is poorly expressed and localized in alpha cells, while its homologue furin is optimally positioned for GLP-1 production. We also note that GLP-1 and glucagon processing occur in different subcellular compartments, creating two distinct pools of secretory granules which respond to similar secretory stimuli.</div></div><div><h3>Conclusion</h3><div>Our study suggests that furin, rather than PC1/3, is positioned to process proglucagon into GLP-1, and despite coming from the same precursor molecule, GLP-1 and glucagon are separately packaged in primary human alpha cells.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102259"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activin receptor type IIA/IIB blockade increases muscle mass and strength, but compromises glycemic control in mice","authors":"Michala Carlsson ,&nbsp;Emma Frank ,&nbsp;Joan M. Màrmol ,&nbsp;Mona Sadek Ali ,&nbsp;Steffen H. Raun ,&nbsp;Edmund Battey ,&nbsp;Nicoline Resen Andersen ,&nbsp;Andrea Irazoki ,&nbsp;Camilla Lund ,&nbsp;Carlos Henríquez-Olguin ,&nbsp;Martina Kubec Højfeldt ,&nbsp;Pauline Blomquist ,&nbsp;Frederik Duch Bromer ,&nbsp;Gabriele Mocciaro ,&nbsp;Andreas Lodberg ,&nbsp;Christian Brix Folsted Andersen ,&nbsp;Marco Eijken ,&nbsp;Andreas Mæchel Fritzen ,&nbsp;Jonas Roland Knudsen ,&nbsp;Erik A. Richter ,&nbsp;Lykke Sylow","doi":"10.1016/j.molmet.2025.102261","DOIUrl":"10.1016/j.molmet.2025.102261","url":null,"abstract":"<div><h3>Purpose</h3><div>Blocking the Activin receptor type IIA and IIB (ActRIIA/IIB) has clinical potential to increase muscle mass and improve glycemic control in obesity, cancer, and aging. However, the impact of blocking ActRIIA/IIB on strength, metabolic regulation, and insulin action remains unclear.</div></div><div><h3>Methods</h3><div>Here, we investigated the effect of short- (10 mg kg⁻¹ bw, once, 40h) or long-term (10 mg kg⁻¹ bw, twice weekly, 21 days) antibody treatment targeting ActRIIA/IIB (αActRIIA/IIB) in lean and diet-induced obese mice and engineered human muscle tissue.</div></div><div><h3>Results</h3><div>Short-term <span><math><mrow><mi>α</mi></mrow></math></span> ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76–105%. Despite this, <span><math><mi>α</mi></math></span>ActRIIA/IIB-treated mice exhibited 33% elevated blood glucose and glucose intolerance. Long-term αActRIIA/IIB treatment increased muscle mass (+20%) and reduced fat mass (−8%) in obese mice but failed to enhance insulin-stimulated glucose uptake in muscle or adipose tissue. Instead, it induced glucose intolerance, cardiac hypertrophy with glycogen accumulation, and elevated hepatic triacylglycerol and glucose output in response to pyruvate. Concomitantly, long-term <span><math><mrow><mi>α</mi></mrow></math></span>ActRIIA/IIB treatment increased strength (+30%) in mouse soleus muscle and prevented activin A-induced loss of tissue strength in engineered human muscle tissue. Surprisingly, long-term <span><math><mrow><mi>α</mi></mrow></math></span> ActRIIA/IIB treatment lowered volitional running (−250%).</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that, in accordance with human studies, ActRIIA/IIB blockade holds promise for increasing muscle mass, strength, and muscle insulin sensitivity. However, contrary to the improved glycemic control in humans, ActRIIA/IIB blockade in mice causes severe glucose intolerance and lowers voluntary physical activity. Our study underscores the complex metabolic and functional consequences of ActRIIA/IIB blockade, and highlight species differences on glycemic control, which warrant further investigation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102261"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192177","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}