Molecular Metabolism最新文献

{"title":"Hyperactive mTORC1 underlies sex dimorphic progression of MASLD in mice with hepatocyte prohibitin-1 deficiency.","authors":"Amany A Alowaisi, Jolonda C Mahoney, Ran Huo, Islam A Berdaweel, Rachel M Crawford, Kendall J Mallaro, Jared M McLendon, Ethan J Anderson","doi":"10.1016/j.molmet.2026.102458","DOIUrl":"https://doi.org/10.1016/j.molmet.2026.102458","url":null,"abstract":"<p><strong>Background: </strong>Prohibitins-1,2 (PHB1,2) are highly conserved and ubiquitously expressed proteins that form a multimeric ring complex within mitochondrial and plasma membranes where they intimately control cellular growth and metabolism. Prior studies in clinical and experimental models have linked PHB1 deficiency in liver with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), in addition to MASH and hepatocellular carcinoma, though mechanisms remain poorly understood.</p><p><strong>Methods & results: </strong>Mice with hepatocyte-specific PHB1 haploinsufficiency (hPHB1-KD) were maintained on a standard chow diet. Compared with wild-type (WT), male hPHB1-KD mice at 6 months exhibited moderate but significant increases in body fat, systemic insulin resistance and characteristics of MASLD, while female hPHB1-KD mice were unaffected. Comprehensive transcript-/metabolomic analysis of liver tissue in the male hPHB-KD mice revealed up-regulation of glycerolipid metabolism and Lpin1, a phosphatidic acid phosphatase regulated by mTORC1 that critically regulates hepatic lipid metabolism. Markers of mTORC1 activation were increased in liver from male and female hPHB1-KD mice in the fasted state, accompanied by lower AMPKα phosphorylation, and were not responsive to insulin. PHB1 knockdown experiments in AML12 hepatocytes showed that lipid droplet accumulation occurred in parallel with increased cytosolic, but not nuclear, lipin-1 expression. Notably, short-term treatment with mTORC1 inhibitor Torin1 ameliorated liver steatosis and normalized mTORC1 signaling in male hPHB1-KD mice.</p><p><strong>Conclusions: </strong>These findings illustrate novel mechanisms by which PHB1 regulates lipid metabolism and glycemic control in the liver, and further reveal a sex dimorphic role for mTORC1 hyperactivation in pathogenesis of MASLD.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102458"},"PeriodicalIF":6.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194989","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":"Biphasic remodeling of arcuate nucleus perineuronal nets in diet-induced obese mice.","authors":"Alexander Carbonell, Jarrad M Scarlett, Ellie I James, Kendra L Francis, Kathryn Tyler, Tamim J Chiba, Xavier Xong, Michael A Haidar, Spoorthy Siddam, Aarun S Hendrickson, Noah Marzouk, Cristiana J Meuret, Caeley L Bryan, Nina Brandt, Lauren E Gilman, Jeremy M Frey, Vladislav Baglaev, Mauricio D Dorfman, David A Tovar, Gregory J Morton, Joshua P Thaler, Michael W Schwartz, Kimberly M Alonge","doi":"10.1016/j.molmet.2026.102460","DOIUrl":"https://doi.org/10.1016/j.molmet.2026.102460","url":null,"abstract":"<p><p>The hypothalamic arcuate nucleus (ARC) contains neuronal populations crucial to the regulation of energy and glucose homeostasis. Many of these neurons are enmeshed by specialized extracellular matrix structures known as perineuronal nets (PNNs) that are comprised of chondroitin sulfate proteoglycans, including aggrecan (ACAN), and attached chondroitin sulfate-glycosaminoglycans. In mice, the effect of high-fat diet (HFD) to increase the abundance of ARC PNNs has been implicated in obesity- and diabetes-associated metabolic impairments. However, neither the biochemical nature nor the time course of these HFD-induced PNN changes is known. In this current work, we report that the response of ARC PNNs to HFD feeding is biphasic, characterized by a steady increase in abundance during the first ∼3 months, followed by a gradual decrease at later time points, as diet-induced obesity (DIO) becomes more fully established. Our findings suggest that this novel, biphasic patten of PNN remodeling is 1) driven by weight gain rather than by HFD composition per se, 2) specific to the hypothalamic ARC region, and 3) parallels obesity-associated changes in the circulating glucose level. Furthermore, histochemical analysis reveals that the early increase of ARC PNNs is due primarily to changes in CS glycan attachments rather than the underlying proteoglycan core protein, while long-term HFD associates with reductions of both CS glycans and ACAN. This biphasic remodeling process becomes detectable with the onset of excess weight gain and is paralleled by obesity-associated changes in glycemia. Based on these findings, we conclude that in response to HFD feeding, ARC PNNs exhibit a degree of plasticity not seen in other brain areas and that dynamic PNN remodeling associates with changes in peripheral glycemia.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102460"},"PeriodicalIF":6.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194938","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":"Zfp697/ZNF697 is an RNA-binding protein that modulates TGF-β1 signaling and hepatic inflammation in liver disease.","authors":"Stine M Præstholm, Jorge C Correia, Rafael Hoyos Justiniano, Alisson L da Rocha, Aurel B Leuchtmann, Tadas Sereiva, Margareta Porsmyr-Palmertz, Kathrine Rothamel, Dorota Kaminska, Ranjani Sri Ganji, David Potěšil, Zbyněk Zdráhal, Jussi Pihlajamäki, Gene W Yeo, Jorge L Ruas","doi":"10.1016/j.molmet.2026.102457","DOIUrl":"https://doi.org/10.1016/j.molmet.2026.102457","url":null,"abstract":"<p><p>Liver diseases driven by metabolic dysfunction, inflammation, and fibrosis such as metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis (MASH), and acute liver injury represent a growing global health burden. The zinc finger protein Zfp697 (ZNF697 in humans) is a newly identified regulator of inflammation and regeneration in skeletal muscle. Here, we characterize the role of liver Zfp697 and show that its expression is increased in multiple animal models of liver disease. Indeed, Zfp697/ZNF697 transcript levels show a strong positive correlation with several markers of liver inflammation and fibrosis. In line with that, in human and mouse hepatocytes TGF-β1 increases Zfp697 expression, which in turn regulates genes involved in TGF-β1 signaling, chemokine secretion, and immune cell recruitment. In mice, hepatocyte-specific Zfp697 deletion improves glucose tolerance and is associated with the absence of MASH-induced lean mass loss but does not confer uniform hepatoprotection. Biochemical purification of Zfp697 protein interactors and enhanced crosslinking and immunoprecipitation (eCLIP) analyses reveal that Zfp697 interacts with other RNA-binding proteins and associates with over 1,000 RNAs in mouse liver. Zfp697-associated RNAs include several transcript types, with a large representation of mRNAs which group in pathways related to transcriptional regulation, PI3K/AKT signaling, and cell differentiation. These findings identify Zfp697 as a novel RNA-interacting protein and modulator of TGF-β signaling in the liver and provide a basis for further investigation of its role in liver disease.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102457"},"PeriodicalIF":6.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182535","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":"Hepatic retromer is essential for systemic cholesterol homeostasis by regulating lysosomal cholesterol handling.","authors":"Cristy R C Verzijl, Markus G Barbosa, Dyonne Y Vos, Andries H Heida, Amandine Caillaud, Lauri Vanharanta, Xiaoke Ge, Joël J Tissink, Mirjam H Koster, Marieke Smit, Nicolette Huijkman, Niels J Kloosterhuis, Aurore Girardeau, Zoé Begué-Racapé, Vincent W Bloks, Rick Havinga, Marceline M Fuh, Fulvio Reggiori, Muriel Mari, Ludger Scheja, Folkert Kuipers, Santiago Solé-Domènech, Sander Kooijman, Joerg Heeren, Jan Freark de Boer, Patrick C N Rensen, Elina Ikonen, Antoine Rimbert, Justina C Wolters, Jan Albert Kuivenhoven, Bart van de Sluis","doi":"10.1016/j.molmet.2026.102456","DOIUrl":"10.1016/j.molmet.2026.102456","url":null,"abstract":"<p><p>Disturbed hepatic cholesterol homeostasis is associated with atherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction-associated steatotic liver disease (MASLD). The endo-lysosomal system plays a central role in cholesterol uptake and intracellular trafficking, yet the molecular mechanisms governing these processes remain poorly understood. Here, we identify hepatic vacuolar protein sorting 35 (VPS35), a core component of the retromer complex, as a critical regulator of hepatocellular and systemic cholesterol homeostasis. Liver-specific VPS35 ablation in mice elevated plasma and hepatic cholesterol levels due to impaired hepatic uptake of atherogenic lipoproteins, defective cholesterol trafficking through the endo-lysosomal system, and increased de novo cholesterol biosynthesis. The decreased hepatic uptake of atherogenic lipoproteins was associated with altered subcellular distribution of the low-density lipoprotein receptor (LDLR) and reduced levels of LDLR-related protein 1 (LRP1). The increased hepatic cholesterol content was associated with altered lysosomal ultrastructure and pH and decreased levels of a wide range of lysosomal proteins, including key proteins for lysosomal cholesterol egress, such as lysosomal acid lipase (LAL), scavenger receptor class B member 2 (SCARB2), Niemann-Pick type C1 (NPC1), and NPC2. Collectively, these findings reveal a previously unrecognized function of the hepatic retromer complex in systemic cholesterol homeostasis. Beyond its established role in endosomal cargo transport, VPS35 is essential for lysosomal cholesterol handling by preserving key proteins involved in lysosomal cholesterol metabolism.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102456"},"PeriodicalIF":6.3,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172320","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":"Parabrachial CGRP neurons mediate incretin-induced aversion and anti-aversion, but not anorexia or weight loss.","authors":"Haley S Province, Nathan A Leong, Nicholas J Conley, Nikolas W Hayes, Esther Tang, Lisa R Beutler","doi":"10.1016/j.molmet.2026.102453","DOIUrl":"10.1016/j.molmet.2026.102453","url":null,"abstract":"<p><p>Incretin mimetics such as the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide cause decreased food intake, weight loss, and aversion. Here, we examined the extent to which parabrachial calcitonin gene-related peptide (CGRP) neurons contribute to these effects. Further, we assessed whether glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism alters liraglutide-induced behavior and CGRP neuron activity. We found that liraglutide activates parabrachial CGRP neurons and that this is required for liraglutide-induced aversion, but not anorexia or weight loss. Additionally, treatment with a GIPR agonist (GIPRA) or the well-established anti-emetic drug ondansetron ameliorated liraglutide-induced conditioned taste avoidance (CTA) and CGRP neuron activation without affecting acute liraglutide-induced feeding suppression. Taken together, our findings demonstrate that the aversive and anorexigenic effects of liraglutide are mediated by distinct neural mechanisms that can be separably manipulated. Our findings also highlight GIPR agonism as an emerging anti-aversive approach to GLP-1RA-induced malaise while maintaining the beneficial metabolic effects.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102453"},"PeriodicalIF":6.3,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112194","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":"Cell-type-specific repression reveals MC4R neurons as a site of action for ciliary obesity genes.","authors":"Abbey Diener Blake, Zhixuan Zhang, Coralie Alexandre, Anne Gorayeb, Mrinaalini Jain, Qi Liu, Rithu Pattali, Alicja Bednarska, Parleen Kaur Pandher, Sumei Zhang, Xinyu Yue, James Nuñez, Christian Vaisse","doi":"10.1016/j.molmet.2026.102454","DOIUrl":"10.1016/j.molmet.2026.102454","url":null,"abstract":"<p><strong>Objectives: </strong>Understanding how obesity-associated genes function within defined neuronal subpopulations remains a major barrier to translating human genetics into pathophysiological mechanisms. Melanocortin-4 receptor-expressing (MC4R) neurons are key regulators of energy homeostasis and represent a potential site of action for these genes. Here, we investigated whether obesity-associated ciliary genes regulate body weight through MC4R neurons in vivo, using a Cre-dependent CRISPR interference (CRISPRi) strategy that enables temporal, spatial, and cell-type-specific gene repression without permanent DNA modification.</p><p><strong>Methods: </strong>Gene repression was achieved in MC4R neurons using a Cre-dependent CRISPRi system with AAV-delivered sgRNAs, and physiological outcomes, including body weight and body composition, were assessed following gene downregulation.</p><p><strong>Results: </strong>CRISPRi-mediated repression of Mc4r in adult PVN^MC4R neurons reduced transcript and protein levels and induced progressive obesity, validating the approach. Downregulation of the ciliary adenylyl cyclase Adcy3 specifically in adult PVN^MC4R neurons was sufficient to drive weight gain, establishing a cell-type-specific requirement for ADCY3 in body-weight regulation. An in vivo CRISPRi screen of obesity-associated ciliopathy genes (Bbs10, Inpp5e, Ankrd26) demonstrated that their repression in MC4R neurons is sufficient to promote obesity, identifying these neurons as a convergent site linking human ciliopathies to obesity.</p><p><strong>Conclusions: </strong>These findings define MC4R neurons as a critical neuronal population through which multiple obesity-associated ciliary genes act and establish a direct link between ciliary function in defined neuronal populations and organismal energy balance. This work provides insight into the neural mechanisms underlying obesity and a framework for linking human genetic variations to specific neuronal populations in vivo.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102454"},"PeriodicalIF":6.3,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112205","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":"Modelling G protein-biased agonism using GLP-1 receptor C-terminal mutations","authors":"Hanh Duyen Tran ,&nbsp;Yiming Zuo ,&nbsp;Carissa Wong ,&nbsp;Alice Pollard ,&nbsp;Steve Bloom ,&nbsp;Ben Jones","doi":"10.1016/j.molmet.2026.102321","DOIUrl":"10.1016/j.molmet.2026.102321","url":null,"abstract":"<div><h3>Background and aim</h3><div>The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for type 2 diabetes and obesity. Agonists showing bias in favour of G protein signalling over β-arrestin recruitment and GLP-1R internalisation, e.g. tirzepatide and orforglipron, have favourable clinical efficacy profiles. However, understanding of the effects of biased agonism has been hampered by differences in ligand properties such as affinity, efficacy, stability and pharmacokinetics. Here we used GLP-1R C-tail mutations that inhibit phosphorylation to mimic G protein-biased GLP-1R agonism without the need for ligand modifications.</div></div><div><h3>Methods</h3><div>Serine doublet phosphorylation sites in the human and mouse GLP-1R C-tails were mutated to alanine. Wild-type and mutant GLP-1Rs were examined for β-arrestin recruitment, internalisation, Gα_s activation, and signalling readouts in HEK293 cells and pancreatic β-cell models. Native GLP-1 plus oppositely biased ligands exendin-phe1 (ExF1; G protein-biased) and exendin-asp3 (ExD3; β-arrestin-biased) were used to compare ligand- and receptor-mediated biased agonism.</div></div><div><h3>Results</h3><div>Loss of three C-terminal phosphorylation sites reduced GLP-1- and ExD3-mediated GLP-1R internalisation and β-arrestin recruitment to that seen with ExF1. The phosphodeficient GLP-1R showed preferential plasma membrane Gα_s activation over longer stimulations, with associated increases in whole cell cAMP generation and kinomic signalling. The distal GLP-1R phosphorylation site played a larger role in β-arrestin recruitment, and the proximal sites were more important for GLP-1R internalisation and regulating cAMP production.</div></div><div><h3>Conclusions</h3><div>Genetic changes that reduce β-arrestin recruitment and slow GLP-1R internalisation can enhance GLP-1R signalling, providing conceptual support for the use of G protein bias to improve GLP-1R agonist efficacy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102321"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030056","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":"Maternal BCAA overnutrition programs persistent dysglycemia in lean adult offspring","authors":"Joyce Tzeng ,&nbsp;Ismael Ferrer ,&nbsp;Damaris N. Lorenzo","doi":"10.1016/j.molmet.2026.102331","DOIUrl":"10.1016/j.molmet.2026.102331","url":null,"abstract":"<div><div>Maternal nutrition exerts profound, lasting effects on offspring metabolic health, yet the impact of maternal overconsumption of key nutrients such as branched-chain amino acid (BCAAs) remains poorly understood. Here, we show that intake of a BCAA-enriched isocaloric, protein content-matched diet throughout pregnancy and lactation induces hyperglycemia and altered circulating amino acid profiles in mouse dams, and programs lasting changes in offspring glucose homeostasis. Adult offspring of both sexes on a chow diet exhibited glucose intolerance. Male offspring showed fasting hyperglycemia despite normal adiposity, whereas females maintained normoglycemia via compensatory hyperinsulinemia. Under a postweaning high-fat diet challenge, offspring of BCAA-fed dams were protected from adiposity and hepatic steatosis, yet developed exacerbated hyperglycemia and glucose intolerance. Mechanistically, maternal BCAA overnutrition reprogrammed offspring energy substrate handling through enhanced white adipose tissue lipolysis and fatty acid oxidation, reduced hepatic fatty acid uptake, and increased hepatic oxidative and gluconeogenic capacity. Elevated hepatic PGC-1α served as a central integrator of oxidative and gluconeogenic pathways, uncoupling lipid and glucose metabolism. These findings identify excess maternal BCAA intake as a nutrient-specific driver of developmental programming that uncouples adiposity from glycemic control, highlighting amino acid-driven metabolic plasticity as a critical axis in intergenerational metabolic dysfunction.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102331"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137779","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":"Maternal obesity decreases offspring lifespan","authors":"Eric Moore ,&nbsp;Ramasamy Selvarani ,&nbsp;Kavitha Kurup ,&nbsp;Michael Chan ,&nbsp;Mani Saminathan ,&nbsp;Natesan Pazhanivel ,&nbsp;Kai Ding ,&nbsp;Alexandra Ford ,&nbsp;Brianne M. Taylor ,&nbsp;Karen Jonscher ,&nbsp;Arlan Richardson ,&nbsp;Jacob E. Friedman ,&nbsp;Archana Unnikrishnan","doi":"10.1016/j.molmet.2026.102333","DOIUrl":"10.1016/j.molmet.2026.102333","url":null,"abstract":"<div><div>Data in mice, nonhuman primates, and in humans demonstrate that exposure to maternal obesity increases the risk of multiple diseases in offspring. However, little is known about the aging effects of maternal obesity on the offspring. This study shows that maternal obesity significantly reduced the lifespan of both male and female mice born to obese dams despite being weaned onto a healthy diet at three weeks of age. This reduction in longevity was linked to an increase in age-related fibrotic pathology across multiple organs, e.g., liver, heart, and kidney. Gompertz analysis of the lifespan data showed that maternal obesity offspring have reduced lifespan due to detrimental changes established early during development rather than factors that modify aging later-in-life. These findings are translationally significant as they demonstrate that the growing prevalence of MO may lead to a decrease in overall lifespan and increase in age-related diseases in the next generation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102333"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181174","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":"Selective deletion of FGFR1 in AgRP neurons impairs energy homeostasis under high-fat diet in mice","authors":"Daniel Shookster ,&nbsp;Shea O'Connell ,&nbsp;Patel Darshan ,&nbsp;Taylor Landry ,&nbsp;Wyatt Bunner ,&nbsp;Zhiying Jiang ,&nbsp;Qingchun Tong ,&nbsp;Hu Huang","doi":"10.1016/j.molmet.2026.102332","DOIUrl":"10.1016/j.molmet.2026.102332","url":null,"abstract":"<div><h3>Background</h3><div>The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined.</div></div><div><h3>Methods</h3><div>To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models.</div></div><div><h3>Results</h3><div>Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 loss increased the intrinsic firing rate of AgRP neurons and abolished the suppressive effect of α-Klotho on their activity. At the molecular level, FGFR1 knockdown decreased phosphorylation of the transcription factor FOXO1 and elevated AgRP mRNA expression.</div></div><div><h3>Conclusions</h3><div>Our results define a crucial FGFR1 signaling axis in AgRP neurons that coordinately regulates their electrical activity and peptide expression, thereby establishing FGFR1 as an essential regulator of energy homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102332"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181164","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}