Molecular Metabolism最新文献

{"title":"Prolonged fasting promotes systemic inflammation and platelet activation in humans: A medically supervised, water-only fasting and refeeding study","authors":"Serena Commissati ,&nbsp;Maria Lastra Cagigas ,&nbsp;Andrius Masedunskas ,&nbsp;Giovanna Petrucci ,&nbsp;Valeria Tosti ,&nbsp;Isabella De Ciutiis ,&nbsp;Gayathiri Rajakumar ,&nbsp;Kristopher M. Kirmess ,&nbsp;Matthew R. Meyer ,&nbsp;Alan Goldhamer ,&nbsp;Brian K. Kennedy ,&nbsp;Duaa Hatem ,&nbsp;Bianca Rocca ,&nbsp;Giovanni Fiorito ,&nbsp;Luigi Fontana","doi":"10.1016/j.molmet.2025.102152","DOIUrl":"10.1016/j.molmet.2025.102152","url":null,"abstract":"<div><h3>Objective</h3><div>Prolonged fasting (PF), defined as abstaining from energy intake for ≥4 consecutive days, has gained interest as a potential health intervention. However, the biological effects of PF on the plasma proteome are not well understood.</div></div><div><h3>Methods</h3><div>In this study, we investigated the effects of a medically supervised water-only fast (mean duration: 9.8 ± 3.1 days), followed by 5.3 ± 2.4 days of guided refeeding, in 20 middle-aged volunteers (mean age: 52.2 ± 11.8 years; BMI: 28.8 ± 6.4 kg/m²).</div></div><div><h3>Results</h3><div>Fasting resulted in a 7.7% mean weight loss and significant increases in serum beta-hydroxybutyrate (BHB), confirming adherence. Untargeted high-dimensional plasma proteomics (SOMAScan, 1,317 proteins) revealed multiple adaptations to PF, including preservation of skeletal muscle and bone, enhanced lysosomal biogenesis, increased lipid metabolism via PPARα signaling, and reduced amyloid fiber formation. Notably, PF significantly reduced circulating amyloid beta proteins Aβ40 and Aβ42, key components of brain amyloid plaques. In addition, PF induced an acute inflammatory response, characterized by elevated plasma C-reactive protein (CRP), hepcidin, midkine, and interleukin 8 (IL-8), among others. A retrospective cohort analysis of 1,422 individuals undergoing modified fasting confirmed increased CRP levels (from 2.8 ± 0.1 to 4.3 ± 0.2 mg/L). The acute phase response, associated with transforming growth factor (TGF)-β signaling, was accompanied by increased platelet degranulation and upregulation of the complement and coagulation cascade, validated by ELISAs in blood and urine.</div></div><div><h3>Conclusions</h3><div>While the acute inflammatory response during PF may serve as a transient adaptive mechanism, it raises concerns regarding potential cardiometabolic effects that could persist after refeeding. Further investigation is warranted to elucidate the long-term molecular and clinical implications of PF across diverse populations.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102152"},"PeriodicalIF":7.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891315","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":"CPT1C deficiency in SF1 neurons impairs early metabolic adaptation to dietary fats, leading to obesity","authors":"A. Fosch ,&nbsp;D.S. Pizarro ,&nbsp;S. Zagmutt ,&nbsp;A.C. Reguera ,&nbsp;G. Batallé ,&nbsp;M. Rodríguez-García ,&nbsp;J. García-Chica ,&nbsp;O. Freire-Agulleiro ,&nbsp;C. Miralpeix ,&nbsp;P. Zizzari ,&nbsp;D. Serra ,&nbsp;L. Herrero ,&nbsp;M. López ,&nbsp;D. Cota ,&nbsp;R. Rodríguez-Rodríguez ,&nbsp;N. Casals","doi":"10.1016/j.molmet.2025.102155","DOIUrl":"10.1016/j.molmet.2025.102155","url":null,"abstract":"<div><h3>Objectives</h3><div>SF1 neurons of the ventromedial hypothalamus (VMH) play a pivotal role in regulating body weight and adiposity, particularly in response to a high-fat diet (HFD), as well as in the recovery from insulin-induced hypoglycemia. While the brain-specific CPT1C isoform is well known for its role in controlling food intake and energy homeostasis, its function within specific hypothalamic neuronal populations remains largely unexplored. Here, we explore the role of CPT1C in SF1 neurons.</div></div><div><h3>Methods</h3><div>Mice deficient in CPT1C within SF1 neurons were generated, and their response to a HFD was investigated.</div></div><div><h3>Results</h3><div>SF1-<em>Cpt1c</em>-KO mice fail to adjust their caloric intake during initial HFD exposure, which is associated with impaired activation of the melanocortin system. Furthermore, these mice exhibit disrupted metabolic gene expression in the liver, muscle, and adipose tissue, leading to increased adiposity independently of food intake. In contrast, their response to glucose or insulin challenges remains intact. After long-term HFD exposure, SF1-Cpt1c-KO mice are more prone to developing obesity and glucose intolerance than control littermates, with males exhibiting a more severe phenotype. Interestingly, CPT1C deficiency in SF1 neurons also results in elevated hypothalamic endocannabinoid (eCB) levels under both chow and HFD conditions. We propose that this sustained eCB elevation reduces VMH activation by fatty acids and impairs the SF1-POMC drive upon fat intake.</div></div><div><h3>Conclusion</h3><div>Our findings establish CPT1C in SF1 neurons as essential for VMH-driven dietary fat sensing, satiety, and lipid metabolic adaptation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102155"},"PeriodicalIF":7.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887406","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":"Molecular correlates of glycine receptor activity in human β cells","authors":"Amanda Schukarucha Gomes,&nbsp;Cara E. Ellis,&nbsp;Aliya F. Spigelman,&nbsp;Theodore dos Santos,&nbsp;Jasmine Maghera,&nbsp;Kunimasa Suzuki,&nbsp;Patrick E. MacDonald","doi":"10.1016/j.molmet.2025.102156","DOIUrl":"10.1016/j.molmet.2025.102156","url":null,"abstract":"<div><h3>Objectives</h3><div>Glycine acts in an autocrine positive feedback loop in human β cells through its ionotropic receptors (GlyRs). In type 2 diabetes (T2D), islet GlyR activity is impaired by unknown mechanisms. We sought to investigate if the GlyR dysfunction in T2D is replicated by hyperglycemia <em>per se</em>, and to further characterize its action in β cells and islets.</div></div><div><h3>Methods</h3><div>GlyR-mediated currents were measured using whole-cell patch-clamp in human β cells from donors with or without T2D, or after high glucose (15 mM) culture. We also correlated glycine-induced current amplitude with transcript expression levels through patch-seq. The expression of the GlyR α1, α3, and β subunit mRNA splice variants was compared between islets from donors with and without T2D, and after high glucose culture. Insulin secretion from human islets was measured in the presence or absence of the GlyR antagonist strychnine.</div></div><div><h3>Results</h3><div>Although gene expression of GlyRs was decreased in T2D islets, and β cell GlyR-mediated currents were smaller, we found no evidence for a shift in GlyR subunit splicing. Glycine-induced currents are also reduced after 48 h culture of islets from donors without diabetes in high glucose, where we also find the reduction of the α1 subunit expression, but an increase in the α3 subunit. We discovered that glycine-evoked currents are highly heterogeneous amongst β cells, inversely correlate with donor HbA1c, and are significantly correlated to the expression of 92 different transcripts and gene regulatory networks (GRNs) that include CREB3(+), RREB1(+) and ZNF697(+). Finally, glucose-stimulated insulin secretion is decreased in the presence of the GlyR antagonist strychnine.</div></div><div><h3>Conclusions</h3><div>We demonstrate that glucose can modulate GlyR expression, and that the current decrease in T2D is likely due to the receptor gene expression downregulation, and not a change in transcript splicing. Moreover, we define a previously unknown set of genes and regulons that are correlated to GlyR-mediated currents and could be involved in GlyR downregulation in T2D. Among those we validate the negative impact of <em>EIF4EBP1</em> expression on GlyR activity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102156"},"PeriodicalIF":7.0,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876677","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":"Krüppel-like factor 5 remodels lipid metabolism in exercised skeletal muscle","authors":"Konstantin Schneider-Heieck ,&nbsp;Joaquín Pérez-Schindler ,&nbsp;Jonas Blatter ,&nbsp;Laura M. de Smalen ,&nbsp;Wandrille Duchemin ,&nbsp;Stefan A. Steurer ,&nbsp;Bettina Karrer-Cardel ,&nbsp;Danilo Ritz ,&nbsp;Christoph Handschin","doi":"10.1016/j.molmet.2025.102154","DOIUrl":"10.1016/j.molmet.2025.102154","url":null,"abstract":"<div><div>Regular physical activity induces a variety of health benefits, preventing and counteracting diseases caused by a sedentary lifestyle. However, the molecular underpinnings of skeletal muscle plasticity in exercise remain poorly understood. We identified a role of the Krüppel-Like Factor 5 (Klf5) in this process, in particular in the regulation of lipid homeostasis. Surprisingly, gain- and loss-of-function studies in muscle <em>in vivo</em> revealed seemingly opposite functions of Klf5 in the response to an acute exercise bout and chronic training, modulating lipid oxidation and synthesis, respectively. Thus, even though only transiently induced, the function of Klf5 is complex and fundamental for a normal long-term training response. These findings highlight the importance of this mediator of external stress response to adaptive remodeling of skeletal muscle tissue.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102154"},"PeriodicalIF":7.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869703","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":"Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy","authors":"Guanqin Jin ,&nbsp;Shihuang Liu ,&nbsp;Kewei Zheng ,&nbsp;Xiaobo Cheng ,&nbsp;Ranran Chai ,&nbsp;Wei Ye ,&nbsp;Wei Wei ,&nbsp;Yongguo Li ,&nbsp;Ai Huang ,&nbsp;Guiling Li ,&nbsp;Huan Yi ,&nbsp;Yu Kang","doi":"10.1016/j.molmet.2025.102151","DOIUrl":"10.1016/j.molmet.2025.102151","url":null,"abstract":"<div><h3>Objectives</h3><div>The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pivotal target in cancer treatment, driving substantial investigation into PI3K inhibitors (PI3Ki). However, the common on-target adverse effect of hyperglycemia presents a substantial challenge to their clinical application. There is an urgent need to discover an anti-hyperglycemic agent that maintains the efficacy of PI3Ki.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive study to explore the interaction between exogenous hyperinsulinemia and PI3Ki in SKOV3 and OVCAR3 ovarian cancer cell lines. We used Western blotting, CCK-8, and EdU assays to determine the effect of this interaction on cell proliferation. In addition, we evaluated the anti-hyperglycemic effects of dorzagliatin in a PI3Ki-induced hyperglycemic mice model. Cell line-derived xenograft (CDX) models were employed to evaluate the in vivo tumor growth inhibitory effects of combining dorzagliatin with PI3Ki.</div></div><div><h3>Results</h3><div>Western blot analysis demonstrated that insulin activated the AKT/INSR/mTOR pathway, reversing PI3Ki-induced p-AKT inhibition. Insulin also attenuated the anti-proliferative effects of PI3Ki. In the hyperglycemic mouse model, dorzagliatin significantly reduced blood glucose levels compared to controls. The combination therapy group (Dorzagliatin + PI3Ki) in CDX models showed a marked reduction in tumor volume. Dorzagliatin not only mitigated hyperglycemia but also enhanced the anti-tumor effects of PI3Ki. A clinical trial (NCT06117566) in cervical cancer patients supported these findings, showing that dorzagliatin stabilized blood glucose levels, facilitated body weight recovery, and achieved a confirmed partial response (PR).</div></div><div><h3>Conclusions</h3><div>Dorzagliatin shows promise for managing PI3Ki-associated hyperglycemia, thereby enhancing its therapeutic efficacy. The activation of liver glycogen kinase and insulin regulation may be key mechanisms underlying its therapeutic benefits.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102151"},"PeriodicalIF":7.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856012","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":"Acyl CoA-binding protein in brown adipose tissue acts as a negative regulator of adaptive thermogenesis","authors":"Albert Blasco-Roset ,&nbsp;Tania Quesada-López ,&nbsp;Alberto Mestres-Arenas ,&nbsp;Joan Villarroya ,&nbsp;Francisco J. Godoy-Nieto ,&nbsp;Rubén Cereijo ,&nbsp;Celia Rupérez ,&nbsp;Ditte Neess ,&nbsp;Nils J. Færgeman ,&nbsp;Marta Giralt ,&nbsp;Anna Planavila ,&nbsp;Francesc Villarroya","doi":"10.1016/j.molmet.2025.102153","DOIUrl":"10.1016/j.molmet.2025.102153","url":null,"abstract":"<div><h3>Objective</h3><div>Defective activity of brown adipose tissue (BAT) is linked to obesity and cardiometabolic diseases. While much is known regarding the biological signals that trigger BAT thermogenesis, relatively little is known about the repressors that may impair BAT function in physiological and pathological settings. Acyl CoA-binding protein (ACBP; also known as diazepam binding inhibitor, DBI) has intracellular functions related to lipid metabolism and can be secreted to act as a circulating regulatory factor that affects multiple organs. Our objective was to determine the role of ACBP in BAT function.</div></div><div><h3>Methods</h3><div>Experimental models based on the targeted inactivation of the <em>Acbp</em> gene in brown adipocytes, both in vitro and in vivo, as well as brown adipocytes treated with recombinant ACBP, were developed and analyzed for transcriptomic and metabolic changes.</div></div><div><h3>Results</h3><div>ACBP expression and release in BAT are suppressed by noradrenergic cAMP-dependent signals that stimulate thermogenesis. This regulation occurs through gene expression modulation and autophagy-related processes. Mice with targeted ablation of <em>Acbp</em> in brown adipocytes exhibit enhanced BAT thermogenic activity and protection against high-fat diet-induced obesity and glucose intolerance; this is associated with BAT transcriptome changes, including upregulation of BAT thermogenesis-related genes. Treatment of brown adipocytes with exogenous ACBP suppresses oxidative activity, lipolysis, and thermogenesis-related gene expression. ACBP treatment inhibits the noradrenergic-induced phosphorylation of p38 MAP-kinase and CREB, which are major intracellular mediators of brown adipocyte thermogenesis.</div></div><div><h3>Conclusions</h3><div>The ACBP system acts as a crucial auto regulatory repressor of BAT thermogenesis that responds reciprocally to the noradrenergic induction of BAT activity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102153"},"PeriodicalIF":7.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856011","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":"Estrogenic activity of E2-conjugated GLP-1 is mediated by intracellular endolysosomal acidification and estrone metabolism","authors":"Callum Coupland ,&nbsp;Na Sun ,&nbsp;Ahmed Khalil ,&nbsp;Özüm Ezgi Karaoglu ,&nbsp;Arkadiusz Liskiewicz ,&nbsp;Daniela Liskiewicz ,&nbsp;Gerald Grandl ,&nbsp;Seun Akindehin ,&nbsp;Gandhari Maity ,&nbsp;Bin Yang ,&nbsp;Brian Finan ,&nbsp;Patrick Knerr ,&nbsp;Jonathan D. Douros ,&nbsp;Axel Walch ,&nbsp;Richard DiMarchi ,&nbsp;Matthias H. Tschöp ,&nbsp;Timo D. Müller ,&nbsp;Aaron Novikoff","doi":"10.1016/j.molmet.2025.102136","DOIUrl":"10.1016/j.molmet.2025.102136","url":null,"abstract":"<div><h3>Objective</h3><div>Recent modifications to glucagon-like peptide 1 (GLP-1), known for its insulinotropic and satiety-inducing effects, have focused on conjugating small molecules to enable selective delivery into GLP-1R+ tissues to achieve targeted synergy and improved metabolic outcomes. Despite continued advancements in GLP-1/small molecule conjugate strategies, the intracellular mechanisms facilitating concurrent GLP-1R signaling and small molecule cargo release remain poorly understood.</div></div><div><h3>Methods</h3><div>We evaluate an estradiol (E2)-conjugated GLP-1 (GLP-1-CEX/E2) for relative differences in GLP-1R signaling and trafficking, and elucidate endolysosomal dynamics that lead to estrogenic activity using various live-cell, reporter, imaging, and mass-spectrometry techniques.</div></div><div><h3>Results</h3><div>We find GLP-1-CEX/E2 does not differentially activate or traffic the GLP-1R relative to its unconjugated GLP-1 backbone (GLP-1-CEX), but uniquely internalizes the E2 moiety and stimulates estrogenic signaling. Endolysosomal pH-dependent proteolytic activity likely mediates E2 moiety liberation, as evidenced by clear amplification in estrogenic activity following co-administration with lysosomal VATPase activator EN6. The hypothesized liberated metabolite from GLP-1-CEX/E2, E2-3-ether, exhibits partial estrogenic efficacy through ERα, and is predisposed toward estrone-3-sulfate conversion. Finally, we identify relative increases in intracellular E2, estrone, and estrone-3-sulfate following GLP-1-CEX/E2 incubation in GLP-1R+ cells, demonstrating proof-of-principle for desired cargo release.</div></div><div><h3>Conclusion</h3><div>Together, our data suggest that GLP-1-CEX/E2 depends on GLP-1R trafficking and lysosome acidification for estrogenic efficacy, with a likely conversion of the liberated E2-3-ether metabolite into estrone-3-sulfate, resulting in a residual downstream flux into active estradiol. Our current findings aim to improve the understanding of small molecule targeting and the efficacy behind GLP-1/small molecule conjugates.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102136"},"PeriodicalIF":7.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848026","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 key role for parabrachial nucleus CGRP neurons in FGF1-Induced anorexia","authors":"Jarrad M. Scarlett ,&nbsp;Eunsang Hwang ,&nbsp;Nicole E. Richardson ,&nbsp;Caeley L. Bryan ,&nbsp;Ingrid Redford ,&nbsp;Emily Quah ,&nbsp;Erik Tyr R. Odderson ,&nbsp;Pique P. Choi ,&nbsp;Matthew K. Hwang ,&nbsp;Bao Anh Phan ,&nbsp;Kelly Kadlec ,&nbsp;Kimberly M. Alonge ,&nbsp;Gregory J. Morton ,&nbsp;Kevin W. Williams ,&nbsp;Michael W. Schwartz","doi":"10.1016/j.molmet.2025.102138","DOIUrl":"10.1016/j.molmet.2025.102138","url":null,"abstract":"<div><div>In addition to sustained glucose lowering, centrally administered fibroblast growth factor 1 (FGF1) induces a potent but transient anorexia in animal models of type 2 diabetes. To investigate the mechanism(s) underlying this anorexic response, the current work focused on a specific neuronal subset located in the external lateral subdivision of the parabrachial nucleus marked by the expression of calcitonin gene-related peptide (elPBN^CGRP neurons). These neurons can be activated by withdrawal of upstream GABAergic inhibitory input and are implicated as mediators of the adaptive response (including anorexia) to a wide range of aversive stimuli. To determine if FGF1-induced anorexia is associated with elPBN^CGRP neuron activation, we employed adult male <em>Calca</em>^Cre:GFP/+ transgenic mice in which GFP is fused to Cre recombinase driven by the CGRP-encoding gene <em>Calca</em>. Here, we show that FGF1 activates elPBN^CGRP neurons, both after intracerebroventricular (icv) injection in vivo and when applied <em>ex vivo</em> in a slice preparation, and that the mechanism underlying this effect depends upon reduced GABAergic input from neurons lying upstream. Consistent with this interpretation, we report that the anorexic response to icv FGF1 is reduced by ∼70% when elPBN^CGRP neurons are silenced using chemogenetics. Last, we report that effects of icv FGF1 injection on both elPBN^CGRP neuron activity and food intake are strongly attenuated by systemic administration of the GABA_A receptor agonist Bretazenil. We conclude that in adult male mice, elPBN^CGRP neuron activation is a key mediator of FGF1-induced anorexia, and that this activation response is mediated at least in part by withdrawal of GABAergic inhibition.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102138"},"PeriodicalIF":7.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795781","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":"Membrane-associated ring–CH–type finger 2 protects against metabolic dysfunction-associated fatty liver disease by targeting fatty acid synthase","authors":"Dongsheng Ni ,&nbsp;Zhaolai Qi ,&nbsp;Shuang Ma ,&nbsp;Yuefeng Wang ,&nbsp;Dehuan Liang ,&nbsp;Xiyue Zhang ,&nbsp;Yong Man ,&nbsp;Jingzhou Chen ,&nbsp;Kefei Dou ,&nbsp;Guoping Li","doi":"10.1016/j.molmet.2025.102137","DOIUrl":"10.1016/j.molmet.2025.102137","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as an important public health concern that poses a significant threat to human health and imposes a substantial economic burden. Research has demonstrated that ubiquitin ligase-mediated substrate protein ubiquitination is a pivotal factor influencing liver lipid homeostasis and metabolic abnormalities in MAFLD. Nevertheless, the specific enzyme molecules implicated in this regulatory process remain to be elucidated. We have published a transcriptome-overexpressing ubiquitin ligase, membrane-associated ring–CH–type finger 2 (MARCH2), in HepG2 cells, and subsequent reanalysis of these transcriptome data revealed a close association between MARCH2 and lipid metabolism.</div></div><div><h3>Methods</h3><div>By employing a range of methodologies, including recombinant adeno-associated virus (rAAV) transduction, lentiviral transduction, immunoblotting, quantitative PCR, tissue section staining, ubiquitination assays, serum biochemical analysis, immunoprecipitation, and mass spectrometry, this study investigated the functions and mechanisms of MARCH2 in the progression of MAFLD at the molecular, cellular, and organismal levels.</div></div><div><h3>Results</h3><div>Overexpression of MARCH2, but not its catalytically inactive ligase variant, inhibited lipid accumulation in HepG2 cells. Additionally, MARCH2 undergoes K48-linked self-polyubiquitination and subsequent proteasomal degradation in response to oleic acid/palmitic acid stimulation. Furthermore, knockout of MARCH2 exacerbates the progression of MAFLD-related phenotypes, including increased body weight, impaired glucose tolerance, reduced insulin sensitivity, hypercholesterolemia, hepatic lipid accumulation, and steatosis, in high-fat diet-fed mice, irrespective of sex. Mechanistically, MARCH2 facilitates the polyubiquitination and degradation of fatty acid synthase (FASN) in the <em>de novo</em> lipogenesis pathway. And liver-specific overexpression of MARCH2 by rAAV effectively reduces FASN levels and further ameliorates MAFLD in ob/ob mice.</div></div><div><h3>Conclusions</h3><div>MARCH2 undergoes self-ubiquitination and plays an important role in maintaining the liver lipid homeostasis of MAFLD, and drug intervention in the MARCH2-FASN axis is a promising approach for treating systemic metabolic abnormalities in MAFLD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102137"},"PeriodicalIF":7.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795708","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":"Wolfram syndrome 2 gene (CISD2) deficiency disrupts Ca2+-mediated insulin secretion in β-cells","authors":"Zhao-Qing Shen ,&nbsp;Wen-Tai Chiu ,&nbsp;Cheng-Heng Kao ,&nbsp;Yu-Chen Chen ,&nbsp;Li-Hsien Chen ,&nbsp;Tsai-Wen Teng ,&nbsp;Shao-Yu Hsiung ,&nbsp;Tsai-Yu Tzeng ,&nbsp;Chien-Yi Tung ,&nbsp;Chi-Chang Juan ,&nbsp;Ting-Fen Tsai","doi":"10.1016/j.molmet.2025.102140","DOIUrl":"10.1016/j.molmet.2025.102140","url":null,"abstract":"<div><h3>Objective</h3><div>Diabetes, characterized by childhood-onset, autoantibody-negativity and insulin-deficiency, is a major manifestation of Wolfram syndrome 2 (WFS2), which is caused by recessive mutations of CISD2. Nevertheless, the mechanism underlying β-cell dysfunction in WFS2 remains elusive. Here we delineate the essential role of CISD2 in β-cells.</div></div><div><h3>Methods</h3><div>We use β-cell specific Cisd2 knockout (Cisd2KO) mice, a CRISPR-mediated Cisd2KO MIN6 β-cell line and transcriptomic analysis.</div></div><div><h3>Results</h3><div>Four findings are pinpointed. Firstly, β-cell specific Cisd2KO in mice disrupts systemic glucose homeostasis via impairing β-granules synthesis and insulin secretion; hypertrophy of the β-islets and the presence of a loss of identity that affects certain β-cells. Secondly, Cisd2 deficiency leads to impairment of glucose-induced extracellular Ca²⁺ influx, which compromises Ca²⁺-mediated insulin secretory signaling, causing mitochondrial dysfunction and, thereby impairing insulin secretion in the MIN6-Cisd2KO β-cells. Thirdly, transcriptomic analysis of β-islets reveals that Cisd2 modulates proteostasis and ER stress, mitochondrial function, insulin secretion and vesicle transport. Finally, the activated state of two potential upstream regulators, Glis3 and Hnf1a, is significantly suppressed under Cisd2 deficiency; notably, their downstream target genes are deeply involved in β-cell function and identity.</div></div><div><h3>Conclusions</h3><div>These findings provide mechanistic insights and form a basis for developing therapeutics for the effective treatment of diabetes in WFS2 patients.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102140"},"PeriodicalIF":7.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795760","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}