Molecular Metabolism最新文献

{"title":"Adipocyte Heparan Sulfate Determines Type 2 Diabetes Susceptibility in Mice via FGF1-Mediated Glucose Regulation.","authors":"Chung-Jui Yu, Ariane R Pessentheiner, Sihao Liu, Sarah Wax, Marissa L Maciej-Hulme, Chelsea D Painter, Bastian Ramms, Daniel R Sandoval, Anthony Quach, Natalie DeForest, G Michelle Ducasa, Chiara Tognaccini, Caroline Labib, Norah Al-Azzam, Friederike Haumann, Greg Trieger, Patrick Secrest, Amit Majithia, Aaron C Petrey, Kamil Godula, Annette R Atkins, Michael Downes, Ronald M Evans, Philip L S M Gordts","doi":"10.1016/j.molmet.2025.102267","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102267","url":null,"abstract":"<p><p>Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102267"},"PeriodicalIF":6.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275255","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, Calum S Vancuylenburg, Riya Shrestha, Ellen M Olzomer, Brenna Osborne, Mingyan Zhou, Suri Zhang, Adam Hargreaves, Frances L Byrne, Kyle L Hoehn","doi":"10.1016/j.molmet.2025.102264","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102264","url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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. Our findings suggest that 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.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102264"},"PeriodicalIF":6.6,"publicationDate":"2025-10-03","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":"Salivary extracellular vesicle-derived microRNAs are related to variances in parameters of obesity, taste and eating behaviour.","authors":"Kristin Röhrborn, Anne Hoffmann, Andrea Lorenz, Peter Kovacs, Tobias Hagemann, Paul Czechowski, Maria Sehm, Annette Horstmann, Michael Stumvoll, Matthias Blüher, Imke Schamarek, Kerstin Rohde-Zimmermann","doi":"10.1016/j.molmet.2025.102265","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102265","url":null,"abstract":"<p><strong>Background: </strong>Extracellular vesicles (EVs), conveyors of microRNAs, have recently been linked to obesity. As taste is a potent driver of eating behaviour and food intake, it's connection to EVs is of increasing interest. This study aimed at deciphering the salivary EV-microRNA profile in relation to taste perception and metabolic pathways of obesity.</p><p><strong>Methods: </strong>Small RNA sequencing was performed on isolated salivary EVs of 90 participants from the Obese-Taste-Bud study. Pathway enrichment and association analyses were conducted to link identified microRNAs to taste recognition, eating behaviour, food intake and various anthropometric-, metabolic- and oral health parameter.</p><p><strong>Results: </strong>The 626 identified microRNAs clustered into pathways related to energy regulation, obesity and diabetes, cell signaling and taste perception. The top three enriched microRNAs are miR-1246, miR-1290 and miR-148a-3p which showed significant associations with fasting blood glucose and cholesterol level, anthropometrics and blood pressure (p<0.05). Additionally, these microRNAs associate with trait eating behaviour (p<0.05). Several other microRNAs were linked to differences in taste recognition scores and are further related to parameters of glucose metabolism and periodontal health, salivary insulin level or food intake (p<0.05).</p><p><strong>Conclusion: </strong>This study, one of the largest on salivary EVs, supports an interrelation of EV's microRNA load with metabolism, eating behaviour and taste recognition offering potential targets for obesity intervention.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102265"},"PeriodicalIF":6.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233021","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":"TERT expression attenuates metabolic disorders in obese mice by promoting adipose stem and progenitor cell expansion and differentiation.","authors":"Laura Braud, Manuel Bernabe, Julien Vernerey, Antonio M A Miranda, Andrea Dominguez, Dmitri Churikov, Manon Richaud, Frédéric Jourquin, Liam Mc Allan, Christophe Lachaud, Jesus Gil, Will Scott, Vincent Géli","doi":"10.1016/j.molmet.2025.102262","DOIUrl":"10.1016/j.molmet.2025.102262","url":null,"abstract":"<p><strong>Background and aims: </strong>Adipose tissue (AT) senescence, induced by obesity or aging, leads to a reduced capacity for tissue remodeling and a chronic pro-inflammatory state, which leads to the onset of metabolic pathologies. Cellular senescence is triggered by various stresses, in particular excessive shortening of telomeres, which activates the p21 pathway and leads to the arrest of the cell cycle. We used the mouse model p21^+/Tert expressing TERT from the Cdkn1a locus to investigate whether counteracting telomere shortening by telomerase (TERT) specifically in pre-senescent cells could improve obesity-induced metabolic disorders.</p><p><strong>Results: </strong>Our study demonstrates that conditional expression of TERT reduces insulin-resistance and glucose intolerance associated with obesity. In AT, this is accompanied by a decrease in the number of senescent p21-positive cells, very short telomeres, and oxidative DNA damage. Single nucleus RNA-seq data reveal TERT expression attenuates senescence induced by HFD in particular in adipose stem and progenitor cells (ASPC). We demonstrate that ASPC expansion and differentiation are promoted in p21^+/Tert obese mice, thereby improving AT plasticity. Furthermore, we show that TERT expression enhances mitochondrial function and alleviates oxidative stress in ASPC. This process contributes to the AT hyperplasia with increased number of adipocytes which has been shown to have a protective effect against obesity-associated metabolic disorders.</p><p><strong>Conclusions: </strong>These results underscore TERT's role in mitigating obesity-related metabolic dysfunction. Conditional TERT expression may therefore represent as a promising therapeutic strategy for obesity-associated metabolic disorders.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102262"},"PeriodicalIF":6.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233108","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":"Oxytocin neurons in the paraventricular and supraoptic hypothalamic nuclei bidirectionally modulate food intake.","authors":"Jessica J Rea, Clarissa M Liu, Anna M R Hayes, Rita Ohan, Grace M Schwartz, Alexander G Bashaw, Molly E Klug, Lea Decarie-Spain, Yedam Park, Alicia E Kao, Valery Grinevich, Scott E Kanoski","doi":"10.1016/j.molmet.2025.102220","DOIUrl":"10.1016/j.molmet.2025.102220","url":null,"abstract":"<p><strong>Objectives: </strong>Oxytocin (OT) is a neuropeptide produced in the paraventricular (PVH) and supraoptic (SON) nuclei of the hypothalamus. Either peripheral or central OT administration reduces food intake through reductions in meal size. However, pharmacological approaches do not differentiate whether OT's influence on food intake is mediated by OT neurons located in the PVH vs. the SON. Here we address this gap using both gain- and loss-of-function approaches targeting OT neurons.</p><p><strong>Methods: </strong>OT neuron-specific designer receptors exclusively activated by designer drugs (DREADDs) were targeted in either the PVH or SON in rats, thus allowing for evaluation of caloric intake following selective activation of OT neurons separately in each nucleus. To examine the physiological role of distinct OT neuron populations in eating behavior, a viral-mediated approach was used to silence synaptic transmission of OT neurons separately in either the PVH or SON.</p><p><strong>Results: </strong>DREADDs-mediated excitation of PVH OT neurons reduced consumption of standard chow via reductions in meal size. On the contrary, SON OT neuron activation had the opposite effect by increasing standard chow consumption. Consistent with these opposing outcomes, activation of PVH and SON OT neurons simultaneously had minimal effects on food intake. Additional results from chronic loss-of-function experiments reveal that PVH OT neuron silencing significantly increased consumption of a high fat and high sugar diet by increasing meal size whereas SON OT neuron silencing reduced chow consumption by decreasing meal size.</p><p><strong>Conclusions: </strong>Collectively these findings suggest that PVH and SON OT neurons differentially modulate food intake by either reducing or increasing caloric consumption, respectively.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102220"},"PeriodicalIF":6.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of hedonic feeding rhythms by circadian clocks in leptin-receptive neurons.","authors":"Jazmin Osorio-Mendoza, Jana-Thabea Kiehn, Sarah Stenger, Keno O Heinen, Laura Griewahn, Christiane E Koch, Undine Haferkamp, Violetta Pilorz, Johanna L Barclay, Parth Joshi, Lisbeth Harder, Olaf Jöhren, Peter Kühnen, Gregor Eichele, Henrik Oster","doi":"10.1016/j.molmet.2025.102221","DOIUrl":"10.1016/j.molmet.2025.102221","url":null,"abstract":"<p><strong>Objective: </strong>The circadian clock anticipates daily repetitive events to adapt physiological processes. In mammals, the circadian system consists of a master clock in the suprachiasmatic nucleus (SCN), which synchronizes subordinate tissue clocks, including extra-SCN central nervous system (CNS) clocks involved in functions such as sleep and appetite regulation. Appetite is controlled by both homeostatic and non-homeostatic (hedonic) circuits. Homeostatic appetite addresses energy needs, while hedonic feeding targets cravings for palatable, calorie-dense foods. The adipokine leptin is a major appetite regulator, interacting with the circadian clock. Although leptin's role in satiation through its action in the mediobasal hypothalamus (MBH) is well established, its involvement in the circadian regulation of feeding remains poorly understood. We hypothesized that circadian gating of leptin signaling in the CNS controls homeostatic and hedonic appetite across the day.</p><p><strong>Methods: </strong>We analyzed food intake rhythms in mice with a loss of leptin (ob/ob mice) or clock function (Per1/2 or Bmal1 KO) and in mice with specific disruption of leptin circadian gating in the CNS (ObRb.Bmal1).</p><p><strong>Results: </strong>We found that in leptin-deficient mice hedonic appetite increases specifically in the early rest phase. In contrast, clock-deficient Per1/2 mutant mice exhibit blunted rhythms in both hedonic and homeostatic appetite control. Finally, when clock function is disrupted in leptin-sensitive neurons only, mice display a lower sensitivity to palatable food, along with reduced initial weight gain and adipose hypertrophy under obesogenic diet conditions.</p><p><strong>Conclusions: </strong>Our data describe a local clock-controlled central leptin gating mechanism that modulates hedonic food intake rhythms and impacts metabolic homeostasis.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102221"},"PeriodicalIF":6.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DIO3 depletion attenuates ovarian cancer growth via reduced glycolysis and alterations in glutamine metabolism.","authors":"Dotan Moskovich, Daniel Beilinson, Amit Rosemarin, Aileen Cohen, Itai Fabian, Tzuri Lifschytz, Bernard Lerer, Govindasamy Mugesh, Maya Gottfried, Osnat Ashur-Fabian","doi":"10.1016/j.molmet.2025.102225","DOIUrl":"10.1016/j.molmet.2025.102225","url":null,"abstract":"<p><strong>Objective: </strong>Metabolic reprogramming emerges as a central driver of therapy resistance and survival disadvantage in ovarian cancer. We recently demonstrated that inhibiting the enzyme Deiodinase type 3 (DIO3) reduces ovarian cancer growth, although the underlying mechanism remains unclear.</p><p><strong>Methods: </strong>We studied DIO3 role in metabolism in genetically manipulated ovarian cancer cells using protein expression analysis, integrative proteomics, endogenous and extracellular metabolomics, metabolic assays including lactate and glutamate secretion, reactive oxygen species (ROS) production and the Seahorse Cell Mito Stress test.</p><p><strong>Results: </strong>We reveled that inhibiting DIO3 suppresses glycolysis while enhancing ATP production through oxidative phosphorylation (OXPHOS). We corroborated these findings using two models of ovarian cancer xenografts, demonstrating a marked reduction in glycolytic proteins upon silencing or inhibiting DIO3 using our first in class small molecule. Moreover, altered glutamine metabolism was also documented, favoring urea cycle and TCA cycle engagement over antioxidant production, accompanied by elevated ROS. Intriguingly, DIO3 depletion in fallopian tube cells, the precursor of HGSOC, displayed distinct metabolic adaptations, including enhanced glycolysis and lipid metabolism, suggesting tissue-specific roles for DIO3.</p><p><strong>Conclusions: </strong>These collective findings position DIO3 as a potential regulator of ovarian cancer metabolism, with implications for targeting this enzyme to disrupt tumor energetics as a novel therapeutic approach.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102225"},"PeriodicalIF":6.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"microRNA-1 regulates metabolic flexibility by programming skeletal muscle pyruvate metabolism\" [Mol Metabol 98 (2025) 1-23/102182].","authors":"Ahmed Ismaeel, Bailey D Peck, McLane M Montgomery, Benjamin I Burke, Jensen Goh, Abigail B Franco, Qin Xia, Katarzyna Goljanek-Whysall, Brian McDonagh, Jared M McLendon, Pieter J Koopmans, Daniel Jacko, Kirill Schaaf, Wilhelm Bloch, Sebastian Gehlert, Kevin A Murach, Kelsey H Fisher-Wellman, Ryan L Boudreau, Yuan Wen, John J McCarthy","doi":"10.1016/j.molmet.2025.102223","DOIUrl":"10.1016/j.molmet.2025.102223","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102223"},"PeriodicalIF":6.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the effects of metformin on gut functions and microbiota and their contribution to improving glucose tolerance in diabetic mice","authors":"Murielle Godet ,&nbsp;Emmanuelle Meugnier ,&nbsp;Oriane Vitalis ,&nbsp;Nadia Bendridi ,&nbsp;Aurélie Vieille-Marchiset ,&nbsp;Nathalie Vega ,&nbsp;Bérengère Benoit ,&nbsp;Claudie Pinteur ,&nbsp;Dominique Rainteau ,&nbsp;David Cheillan ,&nbsp;Marie-Caroline Michalski ,&nbsp;Karim Chikh ,&nbsp;Hubert Vidal","doi":"10.1016/j.molmet.2025.102263","DOIUrl":"10.1016/j.molmet.2025.102263","url":null,"abstract":"<div><h3>Objectives</h3><div>Although the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, increasing evidence points to a pivotal role of the gut. Aiming to clarify whether metformin-induced changes in the intestinal tract directly contribute to metabolic improvement, we evaluated the effects of escalating doses (from 50 to 200 mg/kg/day) of metformin orally administered for 4 weeks in mice made glucose intolerant by ten weeks of high fat high sucrose diet.</div></div><div><h3>Methods</h3><div>Several intestinal parameters were studied, including caecal microbiota composition and bile acids profile, ileal FXR signaling, abundance of GLP1-producing cells and goblet cells and blood metabolome.</div></div><div><h3>Results</h3><div>Metformin restored glucose tolerance, fasting insulinemia and HOMA-IR index in a dose-dependent manner. Only a subset of gut-related effects, including mucus production and GLP-1 expression, exhibited a parallel dose–response relationship, suggesting a possible contribution to the observed metabolic improvements. In contrast, other changes, including ileal Fxr-Fgf15 inhibition and hepatic ceramide reduction did not scale with dose, suggesting they are not the main drivers of metformin dose-dependent effects on glycemic control. We also pointed out marked differential sensitivity of gut bacteria to metformin supporting complex interactions of the drug with the microbial ecosystem.</div></div><div><h3>Conclusion</h3><div>Finally, metformin enhanced the proliferation of intestinal epithelium, resulting in increased length of ileal villi. Altogether, this study offers new insights into the metformin mechanism of action and revealed potential novel microbial biomarkers and targets for enhancing its therapeutic efficacy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102263"},"PeriodicalIF":6.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206910","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, Emma Frank, Joan M Màrmol, Mona Sadek Ali, Steffen H Raun, Edmund Battey, Nicoline Resen Andersen, Andrea Irazoki, Camilla Lund, Carlos Henríquez-Olguin, Martina Kubec Højfeldt, Pauline Blomquist, Frederik Duch Bromer, Gabriele Mocciaro, Andreas Lodber, Christian Brix Folsted Andersen, Marco Eijken, Andreas Mæchel Fritzen, Jonas Roland Knudsen, Erik A Richter, Lykke Sylow","doi":"10.1016/j.molmet.2025.102261","DOIUrl":"10.1016/j.molmet.2025.102261","url":null,"abstract":"<p><strong>Purpose: </strong>Blocking the Activin receptor type IIA and B (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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>Short-term α ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76-105%. Despite this, α 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 α 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 α ActRIIA/IIB treatment lowered volitional running (-250%).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102261"},"PeriodicalIF":6.6,"publicationDate":"2025-09-27","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}