Metabolism: clinical and experimental最新文献

{"title":"Corrigendum to “Prolonged increase in glutamate whole body and intracellular production in older adults with COPD and healthy controls post-resistance exercise” [Metabolism, Volume 168, July 2025, 156185]","authors":"Robert H. Mbilinyi , Nicolaas E.P. Deutz , Clayton L. Cruthirds , Laura E. Ruebush , Tarun Sontam , Gabriella A.M. Ten Have , John J. Thaden , Mariëlle P.K.J. Engelen","doi":"10.1016/j.metabol.2025.156265","DOIUrl":"10.1016/j.metabol.2025.156265","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156265"},"PeriodicalIF":10.8,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UBC9 ameliorates diabetic cardiomyopathy by modulating cardiomyocyte mitophagy through NEDD4/RUNX2/PSEN2 axis","authors":"Hanlin Wu ,&nbsp;Zheming Yang ,&nbsp;Ting Zhou ,&nbsp;Jing Wang ,&nbsp;Yuxin Bu ,&nbsp;Haixu Song ,&nbsp;Chenghui Yan ,&nbsp;Dan Liu ,&nbsp;Yaling Han","doi":"10.1016/j.metabol.2025.156264","DOIUrl":"10.1016/j.metabol.2025.156264","url":null,"abstract":"<div><h3>Aim</h3><div>Diabetic cardiomyopathy (DCM) is one of the most significant cardiovascular complications in patients with diabetes. Ubiquitin conjugating enzyme 9 (UBC9) is the only SUMO-E2 enzyme that plays a key role in cardiomyocytes homeostasis. This study aimed to elucidate the roles and mechanisms of UBC9 in DCM development.</div></div><div><h3>Methods</h3><div>We established cardiomyocyte-specific UBC9 knockout mice and UBC9-overexpressing mice in vivo. A DCM model was established by feeding a high-fat diet and administering a low-dose streptozotocin injection. Proteomics, H&amp;E staining, Sirius Red staining, WGA staining, real-time PCR, and western blotting were performed to examine fibrosis, hypertrophy, and mitophagy in the myocardium. Neonatal mouse cardiomyocytes (NMCMs) were cultured in vitro and stimulated with palmitic acid, UBC9 overexpression adenovirus, and small interfering RNA to establish UBC9 overexpression or knockdown NMCMs. Real-time PCR, western blotting, and immunoprecipitation were employed to examine the roles and mechanisms of UBC9 in cardiomyocyte mitophagy.</div></div><div><h3>Results</h3><div>The transcription and protein levels of UBC9 were significantly decreased in the myocardium of DCM mice. Cardiomyocyte-specific UBC9 knockout aggravated cardiac dysfunction, myocardial fibrosis, hypertrophy, and impaired mitophagy. Conversely, UBC9 overexpression produced opposite effects. UBC9 protected cardiomyocyte mitophagy independently of SUMOylation. UBC9 exerted protective effects against defective cardiomyocyte mitophagy by directly binding to NEDD4, enhancing RUNX2 ubiquitination and degradation, which in turn increased PSEN2 expression. Moreover, the impact of UBC9 on cardiomyocyte mitophagy was reversed upon PSEN2 knockdown.</div></div><div><h3>Conclusions</h3><div>UBC9 alleviated DCM development through the NEDD4/RUNX2/PSEN2 pathway. These findings offer novel insights into the potential of UBC9 as a therapeutic target for DCM.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156264"},"PeriodicalIF":10.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical activation of adipose tissue macrophages mediated by Piezo1 protects against diet-induced obesity by regulating sympathetic activity","authors":"Shaoqiu Leng ,&nbsp;Xiaoyu Zhang ,&nbsp;Ruxia Zhao ,&nbsp;Nan Jiang ,&nbsp;Xinyue Liu ,&nbsp;Xin Li ,&nbsp;Qi Feng ,&nbsp;Zi Sheng ,&nbsp;Shuwen Wang ,&nbsp;Jun Peng ,&nbsp;Xiang Hu","doi":"10.1016/j.metabol.2025.156262","DOIUrl":"10.1016/j.metabol.2025.156262","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity-induced mechanical changes in white adipose tissue (WAT), including adipocyte hypertrophy and fibrosis, are hypothesized to alter adipose tissue macrophage (ATM) function through mechanosensitive pathways. This study aimed to determine whether the mechanosensor Piezo1 in ATMs regulates obesity-associated metabolic dysfunction and thermogenesis.</div></div><div><h3>Methods</h3><div>To investigate macrophage Piezo1 in obesity, myeloid-specific Piezo1-deficient mice (<em>Piezo1</em>^∆lyz2) and littermate controls (<em>Piezo1</em>^flox/+) were fed a high-fat diet (HFD) to induce obesity for 12 weeks. Metabolic assessments (GTT/ITT), tissue analyses (H&amp;E staining, micro-CT), and RNA-seq were performed. Bone marrow transplantation and co-culture experiments (BMDMs with 3T3L1 adipocytes/PC12 neurons) were performed to evaluate macrophage-adipocyte/neuron crosstalk. Sympathetic activity was tested via cold exposure, NE measurement, and 6-OHDA/αMPT denervation. Molecular mechanisms were investigated using ChIP-qPCR.</div></div><div><h3>Results</h3><div><em>Piezo1</em>^∆lyz2 mice exhibited aggravated HFD-induced obesity and insulin resistance despite reduced pro-inflammatory responses. Piezo1 deficiency in ATMs suppressed Slit3–ROBO1 signaling, leading to diminished NE secretion and impaired thermogenesis. Pharmacological inhibition of NE release (6-OHDA) or ROBO1 knockdown (shROBO1) abolished thermogenic disparities between <em>Piezo1</em>^∆lyz2 and control mice. Mechanistically, Piezo1 activation triggered SP1 nuclear translocation, directly binding to the Slit3 promoter to drive Slit3 transcription and secretion.</div></div><div><h3>Conclusion</h3><div>Piezo1 in ATMs mitigates obesity progression by promoting Slit3–ROBO1-dependent NE secretion and thermogenesis, independent of its pro-inflammatory role. This mechanosensitive pathway links WAT mechanical remodeling to metabolic regulation, which may offer a novel approach for managing obesity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156262"},"PeriodicalIF":10.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143823272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reconsidering KLK7's role in adipose inflammation: letter to the editor.","authors":"Yaohui Zhong, Jiaqi Wei, Rui Jiang","doi":"10.1016/j.metabol.2025.156255","DOIUrl":"https://doi.org/10.1016/j.metabol.2025.156255","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156255"},"PeriodicalIF":10.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Propagation of senescent phenotypes by extracellular HMGB1 is dependent on its redox state","authors":"Ji-Won Shin ,&nbsp;Dong-Hyun Jang ,&nbsp;So Young Kim ,&nbsp;Je-Jung Lee ,&nbsp;Tae-Hwan Gil ,&nbsp;Eunha Shim ,&nbsp;Ji Yeon Kim ,&nbsp;Hyeon Soo Kim ,&nbsp;Michael J. Conboy ,&nbsp;Irina M. Conboy ,&nbsp;Christopher D. Wiley ,&nbsp;Jeon-Soo Shin ,&nbsp;Ok Hee Jeon","doi":"10.1016/j.metabol.2025.156259","DOIUrl":"10.1016/j.metabol.2025.156259","url":null,"abstract":"<div><h3>Background &amp; purpose</h3><div>Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype (SASP) factor, exists in various redox states. Here, we investigate the role of redox-sensitive HMGB1 (ReHMGB1) in driving paracrine and systemic senescence.</div></div><div><h3>Methods</h3><div>We applied the paracrine senescence cultured model to evaluate the effect of ReHMGB1 on cellular senescence. Each redox state of HMGB1 was treated extracellularly to assess systemic senescence both <em>in vitro</em> and <em>in vivo</em>. Senescence was determined by SA-β-gal &amp; EdU staining, p16^INK4a and p21 expression, RT-qPCR, and Western blot methods. Bulk RNA sequencing was performed to investigate ReHMGB1-driven transcriptional changes and underlying pathways. Cytokine arrays characterized SASP profiles from ReHMGB1-treated cells. <em>In vivo</em>, young mice were administered ReHMGB1 systemically to induce senescence across multiple tissues. A muscle injury model in middle-aged mice was used to assess the therapeutic efficacy of HMGB1 blockade.</div></div><div><h3>Results</h3><div>Extracellular ReHMGB1, but not its oxidized form, robustly induced senescence-like phenotypes across multiple cell types and tissues. Transcriptomic analysis revealed activation of RAGE-mediated JAK/STAT and NF-κB pathways, driving SASP expression and cell cycle arrest. Cytokine profiling confirmed paracrine senescence features induced by ReHMGB1. ReHMGB1 administration elevated senescence markers <em>in vivo</em>, while HMGB1 inhibition reduced senescence, attenuated systemic inflammation, and enhanced muscle regeneration.</div></div><div><h3>Conclusion</h3><div>ReHMGB1 is a redox-dependent pro-geronic factor driving systemic senescence. Targeting extracellular HMGB1 may offer therapeutic potential for preventing aging-related pathologies.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156259"},"PeriodicalIF":10.8,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A complex multisystem disorder including hypopituitarism and hypoparathyroidism, associated with mutation in the gene encoding fatty acid synthase (FASN)","authors":"L.C. Gregory ,&nbsp;S. Krywawych ,&nbsp;S. Rahman ,&nbsp;Carlos F. Lagos ,&nbsp;S. Eaton ,&nbsp;M.T. Dattani","doi":"10.1016/j.metabol.2025.156256","DOIUrl":"10.1016/j.metabol.2025.156256","url":null,"abstract":"<div><div>Whole exome sequencing performed on a male patient with a complex phenotype including short stature associated with hypopituitarism, sensorineural deafness, hypoparathyroidism, retinal dystrophy, and developmental delay revealed a novel <em>de novo</em> variant in <em>FASN</em> (p.Ala2132Val), encoding fatty acid synthase. The patient failed to respond to growth-promoting treatment, only reaching a height of 128.3 cm (−6.98 SDS) at 24.7 years of age, and was prepubertal with a delayed bone age (13.6 years). Subsequent metabolic investigations demonstrated high triglyceride concentrations throughout an 18 h fast with a failure to increase 3-hydroxybutyrate, suggesting a defect in fatty acid oxidation or ketone body synthesis.</div><div>Human embryonic brain analysis revealed <em>FASN</em> expression in the diencephalon, hypothalamus and Rathke's pouch. Following the labelling of glucose with carbon-13 (C13) in cultured fibroblasts, mass spectrometry data revealed that more C13-glucose was incorporated into <em>de novo</em> synthesised palmitic acid in controls compared to patient cells, suggesting reduced fatty acid synthesis in the patient.</div><div>Our data suggest that the <em>FASN</em> p.Ala2132Val variant is associated with a complex phenotype including hypothalamo-pituitary dysfunction, consistent with previous studies showing that rodent neural/progenitor brain stem cells are governed by Fasn-dependent <em>de novo</em> lipogenesis (fatty acid synthesis) for proliferation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156256"},"PeriodicalIF":10.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction models for the implementation of precision medicine in the real world. Some critical issues.","authors":"Claudia Menzaghi, Massimiliano Copetti, Christos S Mantzoros, Vincenzo Trischitta","doi":"10.1016/j.metabol.2025.156257","DOIUrl":"https://doi.org/10.1016/j.metabol.2025.156257","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156257"},"PeriodicalIF":10.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting gender differences in obesity and type 2 diabetes: Letter to the editor.","authors":"Yaohui Zhong, Jiaqi Wei, Rui Jiang","doi":"10.1016/j.metabol.2025.156260","DOIUrl":"10.1016/j.metabol.2025.156260","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156260"},"PeriodicalIF":10.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling sphingolipid complexity in liver fibrosis: Perspectives for future research.","authors":"Jiaqi Wei, Yaohui Zhong, Yaling Li, Jun Li","doi":"10.1016/j.metabol.2025.156254","DOIUrl":"https://doi.org/10.1016/j.metabol.2025.156254","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156254"},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hexosamine biosynthesis dysfunction-induced LIFR N-glycosylation deficiency exacerbates steatotic liver ischemia/reperfusion injury","authors":"Ran Liu ,&nbsp;Gengqiao Wang ,&nbsp;Yongbing Qian ,&nbsp;Zhengting Jiang ,&nbsp;Weimin Wang ,&nbsp;Mao Cai ,&nbsp;Shuhua Zhang ,&nbsp;Guoliang Wang ,&nbsp;Chuanzheng Wang ,&nbsp;Tianhao Zou ,&nbsp;Huan Cao ,&nbsp;Di Zhang ,&nbsp;Xueling Wang ,&nbsp;Shenghe Deng ,&nbsp;Tongxi Li ,&nbsp;Jinyang Gu","doi":"10.1016/j.metabol.2025.156258","DOIUrl":"10.1016/j.metabol.2025.156258","url":null,"abstract":"<div><h3>Background</h3><div>More and more steatotic livers undergo resection or transplantation but they exhibit higher susceptibility to ischemia-reperfusion injury (IRI), which results in increased perioperative complication morbidity and mortality. IRI is driven by various cytokines and receptors, both of which are extensively modified by N-glycosylation. We aim to elucidate susceptibility of steatotic livers to IRI from the perspective of N-glycosylation.</div></div><div><h3>Methods</h3><div>Differentially expressed genes and glycoproteins were identified with RNA-seq and N-glycoproteomics. Myeloid LIF or hepatocyte LIFR knockout mice were developed to examine the function of LIF and LIFR. Modalities including phosphoproteomics, ChIP-seq, single cell RNA-seq, metabolomics and immunoblotting were utilized to investigate underlying mechanisms.</div></div><div><h3>Results</h3><div>LIF transcription in myeloid cells and LIFR N-glycosylation in hepatocytes were substantially induced by IRI of normal livers. LIF and LIFR protected normal livers from IRI through activating STAT3 and promoting downstream TNFAIP3 expression, which was facilitated by LIFR N-glycosylation. Mechanistically, N-glycosylation at N238 stabilized LIFR protein by disrupting TRIM28-mediated K48 ubiquitination at LIFR K254. Furthermore, N-glycosylation at N358/N658/N675 of LIFR facilitated LIF/LIFR/gp130 complex formation and subsequent signal transduction. However, in steatotic livers, myeloid cell LIF transcription was partially inhibited due to hepatic microenvironment L-arginine insufficiency, while hepatocyte LIFR N-glycosylation was defective due to intracellular UDP-GlcNAc exhaustion. Importantly, combined L-arginine and GlcNAc treatment reversed LIF expression and LIFR N-glycosylation insufficiency, which represents potential therapeutic strategy to protect steatotic livers.</div></div><div><h3>Conclusions</h3><div>LIF expression and LIFR N-glycosylation insufficiency aggravates steatotic liver IRI, which can be reversed by combined L-arginine and GlcNAc treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156258"},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}