Molecular Metabolism最新文献

{"title":"C3aR1 on β cells enhances β cell function and survival to maintain glucose homeostasis","authors":"Renan Pereira de Lima ,&nbsp;Ang Li ,&nbsp;Ankit Gilani ,&nbsp;Alfonso Rubio-Navarro ,&nbsp;Charles D. Warren ,&nbsp;Isabella Y. Kong ,&nbsp;Jacob B. Geri ,&nbsp;James C. Lo","doi":"10.1016/j.molmet.2025.102134","DOIUrl":"10.1016/j.molmet.2025.102134","url":null,"abstract":"<div><h3>Objective</h3><div>Pancreatic β cell dysfunction is critical to the development of type 2 diabetes (T2D). Our previous studies suggested that C3aR1 on β cells promotes insulin secretion and cell survival. However, as C3aR1 is expressed on many other cell types including within the islets, whole-body C3aR1 knockout models confound the analyses of direct impacts on β cells.</div></div><div><h3>Methods</h3><div>To clarify the role of C3aR1 in β cells under T2D conditions, we generated β cell-specific C3aR1 knockout mice. We assessed glucose homeostasis, focusing on β cell function and mass under metabolic stress conditions, to interrogate the effects of C3aR1 on β cells in a mouse model of T2D. We performed proteomic analyses on islets from control and β cell-specific C3aR1 knockout mice. To determine potential translational relevance, <em>C3AR1</em> was assessed alongside glucose-stimulated insulin secretion in human islets.</div></div><div><h3>Results</h3><div>We show that the complement receptor C3aR1 on β cells plays an essential role in maintaining β cell homeostasis, especially under the metabolic duress of obesity and T2D. Male mice with β cell specific deletion of <em>C3ar1</em> (β-C3aR1 KO) exhibit worse glucose tolerance and lower insulin levels when fed regular or high fat diet. Under high fat diet, β-C3aR1 KO also have diminished β cell mass. Islets from β-C3aR1 KO mice demonstrate impaired insulin secretion. β cells lacking C3aR1 display increased susceptibility to lipotoxicity-mediated cell death. Markers of β cell identity are decreased in β-C3aR1 KO mice while stress markers are elevated. Disruption of <em>C3ar1</em> on β cells ablates the insulin secretory response to C3a, establishing a signaling axis between C3a and β cell-derived C3aR1. Islet proteomic analyses highlight the MAPK pathway and mitochondrial dysfunction with C3aR1 loss in β cells. Finally, we show that <em>C3AR1</em> is positively correlated with insulin secretion in human islets.</div></div><div><h3>Conclusions</h3><div>These findings indicate that C3aR1 expression on β cells is necessary to maintain optimal β cell function and preserve β cell mass in T2D.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102134"},"PeriodicalIF":7.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795698","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":"Deubiquitinating enzyme USP2 regulates brown adipose tissue thermogenesis via controlling EBF2 stabilization","authors":"Yuejie Xu ,&nbsp;Ying Chen ,&nbsp;Ningning Bai ,&nbsp;Yingying Su ,&nbsp;Yafen Ye ,&nbsp;Rong Zhang ,&nbsp;Ying Yang ,&nbsp;Caizhi Liu ,&nbsp;Cheng Hu ,&nbsp;Jiemin Pan","doi":"10.1016/j.molmet.2025.102139","DOIUrl":"10.1016/j.molmet.2025.102139","url":null,"abstract":"<div><h3>Objective</h3><div>The activation of brown adipose tissue (BAT) promotes energy expenditure is recognized as a promising therapeutic strategy for combating obesity. The deubiquitinating enzyme family members are widely involved in the process of energy metabolism. However, the specific deubiquitinating enzyme member that affects the BAT thermogenesis remains largely unexplored.</div></div><div><h3>Methods</h3><div>Adeno-associated virus, lentivirus and small molecule inhibitor were applied to generate USP2 gain- or loss-of-function both <em>in vivo</em> and <em>in vitro</em>. OxyMax comprehensive laboratory animal monitoring system, seahorse and transmission electron microscopy were used to determine the energy metabolism. Quantitative proteomics, immunofluorescence staining and co-immunoprecipitation were performed to reveal the potential substrates of USP2.</div></div><div><h3>Results</h3><div>USP2 is upregulated upon thermogenic activation in adipose, and has a close correlation with <em>UCP1</em> mRNA levels in human adipose tissue. BAT-specific Usp2 knockdown or systemic USP2 inhibition resulted in impaired thermogenic programs both <em>in vivo</em> and <em>in vitro</em>. Conversely, overexpression of Usp2 in BAT conferred protection against high-fat diet-induced obesity and associated metabolic disorders. Proteome-wide analysis identified EBF2 as the substrate of USP2 that mediates the thermogenic function of USP2 in BAT.</div></div><div><h3>Conclusions</h3><div>Our data demonstrated the vital role of USP2 in regulating BAT activation and systemic energy homeostasis. Activation of USP2-EBF2 interaction could be a potential therapeutic strategy against obesity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102139"},"PeriodicalIF":7.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795704","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":"Excessive exercise elicits poly (ADP-ribose) Polymerase-1 activation and global protein PARylation driving muscle dysfunction and performance impairment","authors":"Barbara M. Crisol ,&nbsp;Matheus B. Rocha ,&nbsp;Beatriz Franco ,&nbsp;Ana Paula Morelli ,&nbsp;Carlos K. Katashima ,&nbsp;Scylas J.A. Junior ,&nbsp;Fernanda S. Carneiro ,&nbsp;Renata R. Braga ,&nbsp;Rafael S. Brícola ,&nbsp;Graciana de Azambuja ,&nbsp;Raul Gobato Costa ,&nbsp;Andrea M. Esteves ,&nbsp;Marcelo A. Mori ,&nbsp;Maria C.G. Oliveira ,&nbsp;Dennys E. Cintra ,&nbsp;José R. Pauli ,&nbsp;Filip J. Larsen ,&nbsp;Adelino S.R. da Silva ,&nbsp;Eduardo R. Ropelle","doi":"10.1016/j.molmet.2025.102135","DOIUrl":"10.1016/j.molmet.2025.102135","url":null,"abstract":"<div><div>Excessive exercise combined with inadequate recovery time may trigger fatigue, performance impairment, and ultimately the overtraining syndrome. The intramyocellular mechanisms involved in the overtraining syndrome remain only partially known. Here, we combined multi-omics analyses from isogenic BXD mouse strains with a mouse model of overtraining and excessive exercise protocol in mice and humans to evaluate the molecular mechanism involved in the performance impairment induced by excessive exercise. We identified that BXD mouse strains with elevated levels of <em>Parp1</em> gene expression in the skeletal muscle displayed features like overtraining syndrome and abnormal muscle genetic signature. High PARP1 protein content and aberrant PARylation of proteins were detected in the skeletal muscle of overtrained, but not in trained mice. Overtraining syndrome reduced mitochondrial function promoted by exercise training, induced muscle hyperalgesia, reduced muscle fiber size and promoted a similar gene signature of myopathy and atrophy models. Short periods of excessive exercise also increased PARylation in the skeletal muscle of mice and healthy subjects. The pharmacological inhibition of PARP1, using Olaparib, and genetic <em>Parp1</em> ablation, preserved muscle fiber morphology and protected against physical performance impairment and other symptoms of the overtraining syndrome in mice. In conclusion, PARP1 excessive activation is related to muscle abnormalities led by long or short periods of excessive exercise, and here we suggest that PARP1 is a potential target in the treatment and prevention of overtraining syndrome.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102135"},"PeriodicalIF":7.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788579","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":"LOX-1 rewires glutamine ammonia metabolism to drive liver fibrosis","authors":"Ruihua Huang ,&nbsp;Hanyu Cui ,&nbsp;Mohammed Abdulaziz Yahya Ali Alshami ,&nbsp;Chuankui Fu ,&nbsp;Wei Jiang ,&nbsp;Mingyuan Cai ,&nbsp;Shuhan Zhou ,&nbsp;Xiaoyun Zhu ,&nbsp;Changping Hu","doi":"10.1016/j.molmet.2025.102132","DOIUrl":"10.1016/j.molmet.2025.102132","url":null,"abstract":"<div><h3>Objective</h3><div>Liver fibrosis is a crucial condition for evaluating the prognosis of chronic liver disease. Lectin-1ike oxidized low density lipoprotein receptor-1 (LOX-1) has been shown potential research value and therapeutic targeting possibilities in different fibrotic diseases. However, the role of LOX-1 and the underlying mechanisms in liver fibrosis progression remain unclear.</div></div><div><h3>Methods</h3><div>LOX-1 expression was detected in liver tissues from patients and rodents with liver fibrosis. LOX-1 knockout rats were subjected to CCl₄ or methionine and choline-deficient diet (MCD) to induce liver fibrosis. Transcriptomic and metabolomics analysis were used to investigate the involvement and mechanism of LOX-1 on liver fibrosis.</div></div><div><h3>Results</h3><div>We found that LOX-1 exacerbated liver fibrosis by promoting hepatic stellate cells (HSCs) activation. LOX-1 deletion reversed the development of liver fibrosis. We further verified that LOX-1 drove liver fibrosis by reprogramming glutamine metabolism through mediating isoform switching of glutaminase (GLS). Mechanistically, we revealed the crucial role of the LOX-1/OCT1/GLS1 axis in the pathogenesis of liver fibrosis. Moreover, LOX-1 rewired ammonia metabolism by regulating glutamine metabolism–urea cycle to drive the progression of liver fibrosis.</div></div><div><h3>Conclusions</h3><div>Our findings uncover the pivotal role of LOX-1 in the progression of liver fibrosis, enrich the pathological significance of LOX-1 regulation of hepatic ammonia metabolism, and provide an insight into promising targets for the therapeutic strategy of liver fibrosis, demonstrating the potential clinical value of targeting LOX-1 in antifibrotic therapy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102132"},"PeriodicalIF":7.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780512","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":"Adipocyte-derived shed Syndecan-4 suppresses lipolysis contributing to impaired adipose tissue browning and adaptive thermogenesis","authors":"Jiuyu Zong ,&nbsp;Xiaoping Wu ,&nbsp;Xiaowen Huang ,&nbsp;Lufengzi Yuan ,&nbsp;Kai Yuan ,&nbsp;Zixuan Zhang ,&nbsp;Mengxue Jiang ,&nbsp;Zhihui Ping ,&nbsp;Lai Yee Cheong ,&nbsp;Aimin Xu ,&nbsp;Ruby Lai Chong Hoo","doi":"10.1016/j.molmet.2025.102133","DOIUrl":"10.1016/j.molmet.2025.102133","url":null,"abstract":"<div><div>Lipolysis in white adipose tissue (WAT) provides fatty acids as energy substrates for thermogenesis to increase energy expenditure. Syndecan-4 (Sdc4) is a transmembrane proteoglycan bearing heparan sulfate chains. Although single nucleotide polymorphisms (SNPs) of the <em>Sdc4</em> gene have been identified linking to metabolic syndromes, its specific function in adipose tissue remains obscure. Here, we show that Sdc4 serves as a regulator of lipid metabolism and adaptive thermogenesis. Sdc4 expression and shedding are elevated in the white adipose tissue (WAT) of diet-induced obese mice. Adipocyte-specific deletion of <em>Sdc4</em> promotes lipolysis and WAT browning, thereby raising whole-body energy expenditure to protect against diet-induced obesity. Mechanistically, fibroblast growth factor 2 (FGF2) is a paracrine factor that maintains energy homeostasis. Elevated shed Sdc4 concentrates and delivers FGF2 to fibroblast growth factor receptor 1 (FGFR1) on adipocytes, which in turn suppresses lipolysis by reducing hormone-sensitive lipase (HSL) activity, thus exaggerating adipose tissue dysfunction upon high-fat diet induction. Sdc4-deficient adipocytes show higher lipolytic and thermogenic capacity by enhancing HSL phosphorylation and UCP1 expression. Overall, our study reveals that adipocyte-derived shed Sdc4 is a novel suppressor of lipolysis, contributing to decreased energy expenditure, thus exaggerating obesity. Targeting shed Sdc4 is a potential therapeutic strategy for obesity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102133"},"PeriodicalIF":7.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780510","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 GLP-1 analogue optimized for cAMP-biased signaling improves weight loss in obese mice.","authors":"Jonathan D Douros, Aaron Novikoff, Barent DuBois, Rebecca Rohlfs, Jacek Mokrosinski, Wouter F J Hogendorf, Robert Augustin, Myrte Merkestein, Lene Brandt Egaa Martini, Lars Linderoth, Elliot Gerrard, Janos Tibor Kodra, Jenny Norlin, Nikolaj Kulahin Roed, Anouk Oldenburger, Stephanie A Mowery, Maria Waldhoer, Diego Perez-Tilve, Brian Finan, Steffen Reedtz-Runge, Timo D Müller, Patrick J Knerr","doi":"10.1016/j.molmet.2025.102124","DOIUrl":"10.1016/j.molmet.2025.102124","url":null,"abstract":"<p><strong>Objective: </strong>Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism is foundational to modern obesity pharmacotherapies. These compounds were engineered for maximal G protein alpha(s) (Gsα) signaling potency and downstream cAMP production. However, this strategy requires reconsideration as partial, biased GLP-1R agonists characterized by decreased Gsα signaling and disproportionate reductions in β-arrestin recruitment relative to the native ligand provide greater weight loss than full, balanced agonists in preclinical models.</p><p><strong>Methods: </strong>We tested the hypothesis that in vitro signaling bias, which considers both cAMP signaling and β-arrestin recruitment, better predicts weight loss efficacy in diet induced obese (DIO) rodents than cAMP potency alone.</p><p><strong>Results: </strong>Our data demonstrate that signaling bias significantly correlates to GLP-1R agonist mediated weight loss in diet-induced obese mice. We further characterized a protracted GLP-1 analogue (NNC5840) which exhibits a partial-Gsα, cAMP-biased GLP-1R signaling profile in vitro and demonstrates superior maximal body weight reduction compared to semaglutide in DIO mice. The NNC5840 weight loss profile is characterized by reduced in vivo potency but increased maximal efficacy.</p><p><strong>Conclusions: </strong>The data demonstrate that biased agonism is a strong predictor of in vivo efficacy for GLP-1R agonists independent of factors like intrinsic cAMP potency or pharmacokinetics. These data suggest that drug discovery screening strategies which take a holistic approach to target receptor signaling may provide more efficacious candidate molecules. The interpretations of these studies are limited by unknowns including how structural modifications to the biased GLP-1R agonist effect physiochemical properties of the molecules.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102124"},"PeriodicalIF":7.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743307","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":"Sex-dependent effects of FGF21 on HPA axis regulation and adrenal regeneration after Cushing syndrome in mice","authors":"Daniela Díaz-Catalán ,&nbsp;Júlia Capó ,&nbsp;Arturo Vega-Beyhart ,&nbsp;Maria Teresa Rodrigo-Calvo ,&nbsp;Mireia Mora ,&nbsp;Oscar Vidal ,&nbsp;Mattia Squarcia ,&nbsp;Joaquim Enseñat ,&nbsp;Gregori Casals ,&nbsp;Felicia Hanzu","doi":"10.1016/j.molmet.2025.102122","DOIUrl":"10.1016/j.molmet.2025.102122","url":null,"abstract":"<div><h3>Background</h3><div>Cushing's syndrome (CS) results from prolonged exposure to excessive glucocorticoids (GCs), leading to metabolic disturbances and adrenal insufficiency (AI). Fibroblast growth factor 21 (FGF21) has shown promise as a potential therapeutic target for metabolic disorders. This study explores the effects of FGF21 on adrenal gland function in a mouse model of AI following chronic hypercortisolism and investigates sex-dependent differences in the hypothalamic-pituitary-adrenal (HPA) axis response.</div></div><div><h3>Methods</h3><div>We employed a mouse model of AI after chronic corticosterone (CORT) treatment. The effects of recombinant human FGF21 (hFGF21) administration on adrenal function were evaluated in AI mice. Male and female wild-type (WT) and FGF21-overexpressing transgenic (Tg) mice were subjected to 5 weeks of CORT treatment, reaching CS phenotype, followed by immediate analysis or a 10-week recovery period. Metabolic parameters, HPA axis function, and adrenal gland morphology and gene expression were assessed.</div></div><div><h3>Results</h3><div>Prolonged CORT exposure resulted in metabolic disturbances and HPA axis dysregulation. hFGF21 treatment increased CORT and ACTH secretion in AI mice. FGF21 overexpression influenced glucose homeostasis and insulin regulation during CORT treatment and recovery, with sex-specific effects. Tissue-specific regulation of <em>Klb</em> expression was observed across the HPA axis, with distinct patterns between males and females. Tg mice displayed altered adrenal progenitor cell activation and steroidogenic gene expression. Sex-specific differences were observed in adrenal capsule remodeling and gene expression patterns during recovery.</div></div><div><h3>Conclusions</h3><div>This study reveals the complex interplay between FGF21 signaling and GC-induced metabolic and endocrine changes, suggesting a potential sex-specific role of FGF21 in metabolic regulation and HPA axis recovery following after CS.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102122"},"PeriodicalIF":7.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743310","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":"CD73 promotes the immunoregulatory functions of hepatic Tregs through enzymatic and nonenzymatic pathways in MASLD development","authors":"Hua Jin ,&nbsp;Xinjie Zhong ,&nbsp;Chunpan Zhang ,&nbsp;Yongle Wu ,&nbsp;Jie Sun ,&nbsp;Xiyu Wang ,&nbsp;Zeyu Wang ,&nbsp;Jingjing Zhu ,&nbsp;Yuan Jiang ,&nbsp;Xiaonan Du ,&nbsp;Zihan Zhang ,&nbsp;Dong Zhang ,&nbsp;Guangyong Sun","doi":"10.1016/j.molmet.2025.102131","DOIUrl":"10.1016/j.molmet.2025.102131","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading chronic liver disease characterized by chronic inflammation. Regulatory T cells (Tregs) highly express CD73 and play a critical role in modulating the immune response. However, the roles and mechanisms by which CD73 modulates Tregs in MASLD are still unknown. A choline-deficient high-fat diet (CDHFD) or methionine/choline-deficient diet (MCD) was used to establish a MASLD model. We found that CD73 expression was upregulated in Tregs via the FFA-mediated p38/GATA2 signaling pathway. <em>Cd73</em> KO promoted MASLD progression, accompanied by decreased Treg viability and activity. Compared with <em>Cd73</em> KO Tregs, adoptively transferred WT Tregs exhibited increased Treg activity and provided greater protection against hepatic inflammatory responses in MASLD. This immune protection is mediated by CD73 via both enzymatic and nonenzymatic pathways, degrading AMP into ADO to increase Treg function and block DR5-TRAIL-mediated cell death signaling. These findings suggest a potential immunotherapeutic approach for MASLD treatment and highlight its possible relevance for clinical application.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102131"},"PeriodicalIF":7.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730504","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":"A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans","authors":"Brian Finan ,&nbsp;Jonathan D. Douros ,&nbsp;Ronald Goldwater ,&nbsp;Ann Maria Kruse Hansen ,&nbsp;Julie B. Hjerpsted ,&nbsp;Karina Rahr Hjøllund ,&nbsp;Martin K. Kankam ,&nbsp;Patrick J. Knerr ,&nbsp;Anish Konkar ,&nbsp;Stephanie A. Mowery ,&nbsp;Timo D. Müller ,&nbsp;John Rømer Nielsen ,&nbsp;Sune Boris Nygård ,&nbsp;Diego Perez-Tilve ,&nbsp;Kirsten Raun ,&nbsp;Bin Yang ,&nbsp;Matthias H. Tschöp ,&nbsp;Richard D. DiMarchi","doi":"10.1016/j.molmet.2025.102129","DOIUrl":"10.1016/j.molmet.2025.102129","url":null,"abstract":"<div><div>Single molecules that combine complementary modes of action with glucagon-like peptide-1 receptor (GLP-1R) agonism are best-in-class therapeutics for obesity treatment. NN1706 (MAR423, RO6883746) is a fatty-acylated tri-agonist designed for balanced activity at GLP-1R and glucose-dependent insulinotropic peptide receptor (GIPR) with lower relative potency at the glucagon receptor (GcgR). Obese mice, rats and non-human primates dosed with NN1706 showed significant body weight reductions and improved glycemic control. In human participants with overweight or obesity, daily subcutaneous NN1706 treatment resulted in substantial body weight loss in a dose-dependent manner without impairing glycemic control (NCT03095807, NCT03661879). However, increased heart rate was observed across NN1706 treatment cohorts, which challenges further clinical development of NN1706.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102129"},"PeriodicalIF":7.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730503","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":"Semaglutide and bariatric surgery induce distinct changes in the composition of mouse white adipose tissue","authors":"Margo P. Emont ,&nbsp;Adam L. Essene ,&nbsp;Anton Gulko ,&nbsp;Nadejda Bozadjieva-Kramer ,&nbsp;Christopher Jacobs ,&nbsp;Soumya Nagesh ,&nbsp;Randy J. Seeley ,&nbsp;Linus T. Tsai ,&nbsp;Evan D. Rosen","doi":"10.1016/j.molmet.2025.102126","DOIUrl":"10.1016/j.molmet.2025.102126","url":null,"abstract":"<div><div>Adipose tissue is a central player in energy balance and glucose homeostasis, expanding in the face of caloric overload in order to store energy safely. If caloric overload continues unabated, however, adipose tissue becomes dysfunctional, leading to systemic metabolic compromise in the form of insulin resistance and type 2 diabetes. Changes in adipose tissue during the development of metabolic disease are varied and complex, made all the more so by the heterogeneity of cell types within the tissue. Here we present detailed comparisons of atlases of murine WAT in the setting of diet-induced obesity, as well as after weight loss induced by either vertical sleeve gastrectomy (VSG) or treatment with the GLP-1 receptor agonist semaglutide. We focus on identifying populations of cells that return to a lean-like phenotype versus those that persist from the obese state, and examine pathways regulated in these cell types across conditions. These data provide a resource for the study of the cell type changes in WAT during weight loss, and paint a clearer picture of the differences between adipose tissue from lean animals that have never been obese, versus those that have.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102126"},"PeriodicalIF":7.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730506","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}