Molecular Metabolism最新文献

{"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}

{"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}