Christine Mund, Anupam Sinha, Anika Aderhold, Ivona Mateska, Eman Hagag, Sofia Traikov, Bettina Gercken, Andres Soto, Jonathan Pollock, Lilli Arndt, Michele Wölk, Natalie Werner, Georgia Fodelianaki, Pallavi Subramanian, Kyoung-Jin Chung, Sylvia Grossklaus, Mathias Langner, Mohamed Elgendy, Tatyana Grinenko, Ben Wielockx, Andreas Dahl, Martin Gericke, Matthias Blüher, Ünal Coskun, David Voehringer, Maria Fedorova, Mirko Peitzsch, Peter J Murray, Triantafyllos Chavakis, Vasileia Ismini Alexaki
{"title":"A key role of polyamine metabolism in adipose tissue homeostasis that regulates obesity.","authors":"Christine Mund, Anupam Sinha, Anika Aderhold, Ivona Mateska, Eman Hagag, Sofia Traikov, Bettina Gercken, Andres Soto, Jonathan Pollock, Lilli Arndt, Michele Wölk, Natalie Werner, Georgia Fodelianaki, Pallavi Subramanian, Kyoung-Jin Chung, Sylvia Grossklaus, Mathias Langner, Mohamed Elgendy, Tatyana Grinenko, Ben Wielockx, Andreas Dahl, Martin Gericke, Matthias Blüher, Ünal Coskun, David Voehringer, Maria Fedorova, Mirko Peitzsch, Peter J Murray, Triantafyllos Chavakis, Vasileia Ismini Alexaki","doi":"10.1016/j.metabol.2025.156358","DOIUrl":"10.1016/j.metabol.2025.156358","url":null,"abstract":"<p><strong>Background and aims: </strong>Adipose tissue function is integral to systemic metabolic homeostasis. Excessive adipose tissue growth is associated with development of chronic low-grade inflammation and whole body dysmetabolism. The cell metabolic pathways regulating adipose tissue growth and homeostasis are little understood. Here we studied the role of polyamine metabolism in adipose tissue (patho)physiology.</p><p><strong>Methods: </strong>We generated mice with global and adipocyte progenitor (AP)-specific Antizyme inhibitor 2 (AZIN2) deficiency and performed diet-induced obesity studies. APs were isolated from the subcutaneous and gonadal adipose tissue of mice and cultured.</p><p><strong>Results: </strong>Polyamine metabolism components, including AZIN2, were highly expressed in APs and their expression in the adipose tissue was downregulated with obesity. IL4 induced Azin2 expression in APs. AZIN2 facilitated polyamine synthesis and acetylation, and regulated total acetyl-CoA levels in APs. AZIN2 deficiency upregulated histone acetylation in genes related to lipid metabolism. Azin2<sup>-/-</sup> APs committed more efficiently to adipogenesis in vivo and in vitro, and were more prone to senescence compared to wild-type counterparts. Upon diet-induced obesity, global and AP-specific AZIN2 deficiency in mice provoked AP depletion, adipocyte hypertrophy, obesity, inflammation, glucose intolerance and insulin resistance. In human adipose tissue, AZIN2 expression strongly correlated with expression of progenitor markers.</p><p><strong>Conclusions: </strong>Altogether, we identified AZIN2 as a novel AP marker that regulates AP fate and preserves adipose tissue health.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156358"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775789","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}
Mona Hendlinger, Lucia Mastrototaro, Marten Exterkate, Maria Apostolopoulou, Yanislava Karusheva, Geronimo Heilmann, Polina Lipaeva, Klaus Straßburger, Sofiya Gancheva, Sabine Kahl, Michael Roden
{"title":"Exercise training increases skeletal muscle sphingomyelinases and affects mitochondrial quality control in men with type 2 diabetes.","authors":"Mona Hendlinger, Lucia Mastrototaro, Marten Exterkate, Maria Apostolopoulou, Yanislava Karusheva, Geronimo Heilmann, Polina Lipaeva, Klaus Straßburger, Sofiya Gancheva, Sabine Kahl, Michael Roden","doi":"10.1016/j.metabol.2025.156361","DOIUrl":"10.1016/j.metabol.2025.156361","url":null,"abstract":"<p><p>Lipotoxic ceramides (CERs) are implicated in the development of insulin resistance, type 2 diabetes (T2D) and related complications. Exercise training improves insulin sensitivity, potentially via reducing intracellular lipids or enhancing mitochondrial oxidation. Acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin (SM) to CERs, is crucial for muscle repair and development, yet its role in insulin-resistant states and response to exercise remain unclear. We assessed ASM protein and activity, neutral sphingomyelinase (NSM) and sphingolipid species in skeletal muscle of insulin-sensitive (IS, n = 12), insulin-resistant (IR, n = 11) and T2D men (n = 20), before and after a 12-week high-intensity interval training (HIIT). Comprehensive phenotyping comprised hyperinsulinemic-euglycemic clamps, spiroergometry, targeted lipidomics and assessment of markers of mitochondrial quality control. ASM protein was lower at baseline and increased after HIIT only in T2D (p < 0.05), while ASM activity rose across all groups (IS p < 0.01; IR and T2D p < 0.001). HIIT also increased NSM protein in all groups (p < 0.05). Despite lower baseline SM levels in T2D, HIIT led to elevated CERs species in T2D (C16:0, C20:0, C22:0, C24:1, C24:0) and in IR (C16:0, C20:0) (all p < 0.05). Regression analysis suggested that changes in ASM protein and activity relate to changes in mitochondrial fusion and fission as well as AMP-activated protein kinase (AMPK)-mediated mitophagy. In conclusion, HIIT induces expression of both ASM and NSM and alters CER profiles in insulin-resistant skeletal muscle, independently of changes in insulin sensitivity. ASM could therefore rather contribute to exercise-induced mitochondrial remodeling than driving lipotoxicity, warranting further investigation of ASM as a potential target for exercise mimetic therapies.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156361"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784781","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}
Anna Stubbendorff, Suzanne Janzi, Juulia Jukkola, Moa Morency, Shunming Zhang, Yan Borné, Emily Sonestedt
{"title":"Mini-review of the EAT-Lancet planetary health diet and its role in cardiometabolic disease prevention.","authors":"Anna Stubbendorff, Suzanne Janzi, Juulia Jukkola, Moa Morency, Shunming Zhang, Yan Borné, Emily Sonestedt","doi":"10.1016/j.metabol.2025.156373","DOIUrl":"10.1016/j.metabol.2025.156373","url":null,"abstract":"<p><p>Human diets play a crucial role in both human health and environmental sustainability. In 2019, the EAT-Lancet Commission on healthy diets from sustainable food systems introduced the EAT-Lancet planetary health diet, a universal reference diet designed to promote human health while minimizing environmental degradation. It is a predominantly plant-based dietary pattern, rich in whole grains, vegetables, fruits, legumes, and nuts, while low in red meat and added sugars. In this mini-review, we summarize findings from prospective cohorts examining the EAT-Lancet diet in relation to mortality and cardiometabolic outcomes. Higher adherence to this diet was generally associated with lower risk of all-cause mortality, cardiovascular disease, and type 2 diabetes. However, the magnitude of associations varied depending on cohort characteristics, scoring systems, and methodological factors. In addition, adherence to the EAT-Lancet diet was generally low in the studies reviewed. These results suggest potential public health benefits of adopting the EAT-Lancet diet but also highlight the need for harmonized definitions and further research on underlying mechanisms.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156373"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804434","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}
Jiaxing Wang , Qiangzhou Wang , Xinrui Li , Qingqing Cai , Yulin Bi , Chenyang Xu , Hao Bai , Lihong Gu , Guobin Chang , Shihao Chen
{"title":"Emerging roles of TRIM in metabolic regulation","authors":"Jiaxing Wang , Qiangzhou Wang , Xinrui Li , Qingqing Cai , Yulin Bi , Chenyang Xu , Hao Bai , Lihong Gu , Guobin Chang , Shihao Chen","doi":"10.1016/j.metabol.2025.156394","DOIUrl":"10.1016/j.metabol.2025.156394","url":null,"abstract":"<div><div>Recent findings have broadened our understanding of the tripartite motif (TRIM) protein family, positioning these proteins as pivotal regulators of cellular metabolism and cell fate. Primarily functioning as versatile E3 ubiquitin ligases, TRIM proteins orchestrate key metabolic pathways—including glucose, lipid, and amino acid metabolism—through both ubiquitination-dependent and -independent mechanisms such as oligomerization and epigenetic modification. For example, TRIM38, TRIM11, and TRIM24 have been reported to modulate glycolytic flux and insulin signaling by targeting key glucose transporters and glycolytic enzymes, with effects on cancer metabolism and insulin responses in model systems. Similarly, TRIM21 and TRIM56 have been implicated in fatty acid synthesis, oxidation, and cholesterol balance, with potential relevance to fatty-liver conditions and atherosclerosis. Moreover, TRIM-mediated regulation of amino acid metabolism-particularly through pathways involving glutamine and branched-chain amino acids-plays a central role in tumor metabolic reprogramming and survival. Beyond enzymatic regulation, TRIM proteins exert non-canonical functions through epigenetic modulation and interactions with signaling networks. This review synthesizes current insights into the multifaceted roles of TRIM proteins in metabolic control and cell death, suggesting that ferroptosis may link TRIM proteins to lipid and amino acid metabolism, and highlights the connection between TRIM proteins and metabolic stress as a key area for future research.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156394"},"PeriodicalIF":11.9,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109903","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}
Morgane A. Philippe , Blandine Fruchet , Lucie Cagninacci , Lucie Beaudoin , Alexis Gadault , Bastien Aznar , Nicolas Venteclef , Etienne Challet , Agnès Lehuen , Ute C. Rogner , Amine Toubal
{"title":"BMAL2 controls adipose tissue inflammation and metabolic adaptation during obesity","authors":"Morgane A. Philippe , Blandine Fruchet , Lucie Cagninacci , Lucie Beaudoin , Alexis Gadault , Bastien Aznar , Nicolas Venteclef , Etienne Challet , Agnès Lehuen , Ute C. Rogner , Amine Toubal","doi":"10.1016/j.metabol.2025.156396","DOIUrl":"10.1016/j.metabol.2025.156396","url":null,"abstract":"<div><div>Contemporary lifestyle modifications such as changes in nutritional and sleep/wake rhythms increase the risk of metabolic and inflammatory complications linked to obesity, including type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). BMAL2 (Brain and Muscle ARNT Like Protein 2) is a transcription factor belonging to the circadian clock transcriptional feedback loop which synchronizes internal biological rhythms to environment. In humans, reduced expression in white adipose tissue (WAT) and specific polymorphisms of <em>BMAL2</em> are associated with obesity and T2D. In this study we report that <em>Bmal2</em> deletion in mice leads to increased body weight gain during diet-induced obesity. Loss of BMAL2 triggers the inflammatory response by increasing <em>Tnfα</em> expression and modifying adipocyte progenitor fate. This results in reduced lipid storage capacity within the WAT and increased ectopic storage in the liver. These functional and structural alterations culminate in the onset of hepatic steatosis and insulin resistance in liver and WAT. Overall, our investigations underscore the role of BMAL2 in the development and function of adipocytes, as well as in their inflammatory potential within the WAT. Our findings contribute to the understanding of the role of circadian clock genes in obesity and interconnected metabolic complications.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156396"},"PeriodicalIF":11.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124807","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}
Maryam Kay, Anne-Maj Samuelsson, Nike Bharucha, Xueyi Li, Rohin Ramchandani, Rachel E Baum, Diego Ruiz, Aurélie Laguerre, Sherin Lajevardi, Shrikaar Kambhampati, Christian M Metallo, Michael S Kapiloff, Ioannis Karakikes
{"title":"Enhancing cardiac serine biosynthesis mitigates the progression of dilated cardiomyopathy.","authors":"Maryam Kay, Anne-Maj Samuelsson, Nike Bharucha, Xueyi Li, Rohin Ramchandani, Rachel E Baum, Diego Ruiz, Aurélie Laguerre, Sherin Lajevardi, Shrikaar Kambhampati, Christian M Metallo, Michael S Kapiloff, Ioannis Karakikes","doi":"10.1016/j.metabol.2025.156395","DOIUrl":"10.1016/j.metabol.2025.156395","url":null,"abstract":"<p><p>Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. However, disease-modifying therapies remain limited. Metabolic dysfunction has emerged as a key driver of DCM pathogenesis, and impaired serine biosynthesis, catalyzed by the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH), has recently been identified as a potential therapeutic target. Here, we evaluated the therapeutic potential of increasing serine biosynthesis through AAV9-mediated PHGDH gene augmentation in a transgenic TM54 mouse model of DCM with established pathology. Longitudinal echocardiography showed preserved systolic function and prevented ventricular dilatation in TM54 mice treated with AAV9-PHGDH compared to AAV9-GFP controls. Histological analysis revealed reduced myocardial fibrosis and cardiomyocyte hypertrophy in AAV9-PHGDH-treated TM54 hearts, indicating a reversal of pathological remodeling. Metabolic profiling, including targeted metabolomics and in vivo <sup>13</sup>C-glucose tracing analysis, revealed that serine levels increased in hearts treated with AAV9-PHGDH, accompanied by decreases in glucose-derived pyruvate and lactate. At the same time, mitochondrial oxidative metabolism remained intact, indicating a shift of glycolytic carbon towards serine biosynthesis. Collectively, these findings show that enhancing cardiac serine synthesis through PHGDH gene augmentation therapy preserves contractile function and mitigates disease progression in vivo, suggesting a novel metabolic therapeutic strategy for DCM.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156395"},"PeriodicalIF":11.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102795","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}
Filipe S Pereira-Dutra, Julia Cunha Santos, Ellen Kiarely Souza, Rodrigo Vieira Savi, Tamyris S Souza, Helen Gil, Hugo Espinheira-Silva, Felipe Ferraro-Moreira, Guilherme Iack, Tamires Cunha-Fernandes, Tathiany Igreja-Silva, Lohanna Palhinha, Mariana Macedo Campos, Ester Fernanda Terra Souza, Amanda França Cordeiro, Pablo Andrade-Dos-Santos, Douglas Mathias Oliveira, Vinicius Soares Cardoso, Matheus A Rajão, Livia Teixeira, Luciana Souza-Moreira, Maria Fernanda Souza Costa, Patrícia Alves Reis, Patrícia T Bozza
{"title":"Sepsis-induced lipid droplet accumulation enhances antibacterial innate immunity through mechanisms dependent on DGAT-1 and interferon-beta.","authors":"Filipe S Pereira-Dutra, Julia Cunha Santos, Ellen Kiarely Souza, Rodrigo Vieira Savi, Tamyris S Souza, Helen Gil, Hugo Espinheira-Silva, Felipe Ferraro-Moreira, Guilherme Iack, Tamires Cunha-Fernandes, Tathiany Igreja-Silva, Lohanna Palhinha, Mariana Macedo Campos, Ester Fernanda Terra Souza, Amanda França Cordeiro, Pablo Andrade-Dos-Santos, Douglas Mathias Oliveira, Vinicius Soares Cardoso, Matheus A Rajão, Livia Teixeira, Luciana Souza-Moreira, Maria Fernanda Souza Costa, Patrícia Alves Reis, Patrícia T Bozza","doi":"10.1016/j.metabol.2025.156389","DOIUrl":"https://doi.org/10.1016/j.metabol.2025.156389","url":null,"abstract":"<p><p>Lipid droplets (LDs) are lipid-rich organelles recognized as central players in lipid homeostasis, signaling, and inflammation. While their functions in inflammation are well-documented, the mechanisms of LDs in antibacterial immunity and infection resistance remain less understood. Our results show that E. coli-infection trigger immunometabolic reprogramming and LD accumulation in macrophages. Moreover, purified LDs from LPS-stimulated and E. coli-infected macrophages exhibited direct E. coli anti-bacterial activity. Pharmacological inhibition or genetic knockdown of DGAT1, a key enzyme in triglyceride synthesis, reduced LD formation, bacterial clearance, and pro-inflammatory responses (nitric oxide, PGE<sub>2</sub>, CCL2, IL-6). Notably, DGAT1 inhibition impaired the expression of IFN-β and several interferon-stimulated genes (ISGs), including viperin, iNOS, cathelicidin and IGTP, in E. coli-infected macrophages. In a cecal-ligation and puncture model of sepsis in C57BL/6 mice, DGAT1 inhibition reduced sepsis-induced LD accumulation in peritoneal cells and decreased levels of IFN-β, CCL2, nitric oxide, and lipid mediators (PGE<sub>2</sub>, LTB<sub>4</sub>, and RvD1). Furthermore, DGAT1 inhibition accelerated sepsis-related mortality, coinciding with elevated bacterial loads in the peritoneum and bloodstream at 6- and 24-h post-sepsis. Our results demonstrate that LDs are critical regulators of innate immunity infection resistance, contributing to both bacterial clearance and the coordination of a protective proinflammatory response during sepsis through mechanisms dependent on DGAT-1 and Type I IFN.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156389"},"PeriodicalIF":11.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091961","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}
Shuman Ran , Siqi Wang , Qi Jin , Genzheng Liu , Xiaobin Xue , Peng Qu , Liang Peng , Hua Meng
{"title":"Emerging role of E4BP4/NFIL3 in metabolic homeostasis","authors":"Shuman Ran , Siqi Wang , Qi Jin , Genzheng Liu , Xiaobin Xue , Peng Qu , Liang Peng , Hua Meng","doi":"10.1016/j.metabol.2025.156390","DOIUrl":"10.1016/j.metabol.2025.156390","url":null,"abstract":"<div><div>E4BP4/NFIL3 (E4 promoter-binding protein 4 or nuclear factor interleukin-3-regulated protein), is well-established for its association with circadian rhythm regulation and immune function. Recent advances in research have revealed its emerging and indispensable role in metabolic homeostasis, positioning it at the crossroads of circadian biology, immune responses, and metabolic balance. This review summarizes three decades of research on E4BP4/NFIL3 and explores its structural basis and regulatory functions. We synthesized current insights into the regulatory pathways that govern E4BP4/NFIL3 and discuss its central role in various metabolic scenarios, emphasizing its emerging significance as a pivotal metabolic regulator. Finally, we identify critical, unresolved questions and propose future research directions to enhance our understanding of E4BP4/NFIL3's broader implications in metabolic health.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156390"},"PeriodicalIF":11.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086404","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}
Thiago dos Reis Araujo , Joel Alves da Silva Junior , Bruna Lourençoni Alves , Dimitrius Santiago Passos Simões Fróes Guimarães , Lohanna Monali Barreto , Mariana Roberta Rodrigues Muniz , Jennifer Rieusset , Everardo Magalhães Carneiro
{"title":"Disruption of mitochondria-associated membranes contributes to the dysregulation of insulin secretion in undernutrition, obesity, and double burden of malnutrition","authors":"Thiago dos Reis Araujo , Joel Alves da Silva Junior , Bruna Lourençoni Alves , Dimitrius Santiago Passos Simões Fróes Guimarães , Lohanna Monali Barreto , Mariana Roberta Rodrigues Muniz , Jennifer Rieusset , Everardo Magalhães Carneiro","doi":"10.1016/j.metabol.2025.156393","DOIUrl":"10.1016/j.metabol.2025.156393","url":null,"abstract":"<div><h3>Aims/hypothesis</h3><div>Nutritional disorders directly affect the endocrine pancreas, increasing the susceptibility to type 2 diabetes mellitus. However, the molecular mechanisms underlying these alterations remain unknown. This study aims to characterize the role of endoplasmic reticulum (ER)-mitochondria contact sites, known as mitochondrial-associated membranes (MAMs), in insulin secretion dysfunctions associated with undernutrition, obesity, and the double burden of malnutrition (DBM).</div></div><div><h3>Methods</h3><div>Rat pancreatic INS-1E β-cells were cultured in a medium without amino acids supplemented with 1 × (control) or 0.25 × (amino acid restriction) of an amino acid solution for 48 h, and then cells were exposed to a fatty acid mix for 48 h. Male C57BL/6 mice were fed a normoprotein diet (14 % protein) or protein-restricted diet (6 % protein) for 6 weeks and subsequently a high-fat diet (35 % kcal) for 12 weeks. ER-mitochondria interactions were evaluated by in situ proximity ligation assay and transmission electronic microscopy.</div></div><div><h3>Results</h3><div>Our findings indicate that protein restriction reduces ER-mitochondria contacts in pancreatic beta-cells, leading to decreased mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). In contrast, obesity increases ER-mitochondria contact points, mitochondrial metabolism, and GSIS in pancreatic beta-cells, without alterations in viability. DBM results in a significant increase in ER-mitochondria contacts, elevated mitochondrial calcium levels, increased production of reactive oxygen species, and cell death, collectively contributing to impaired GSIS response in the context of obesity.</div></div><div><h3>Conclusions/interpretation</h3><div>These data indicates that MAMs play a crucial role in GSIS during nutritional disorders such as undernutrition, obesity, and DBM. Importantly, changes in MAMs precede GSIS impairment, therefore targeting these interactions might prevent further disruption in beta-cell function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156393"},"PeriodicalIF":11.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081075","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}
Jinni Yang , Xue Yang , Yuan Zheng , Anhui Wang , Ziwen Kong , Qinwen Xiao , Yuan Tian , Haijuan Dong , Zunjian Zhang , Min Wang , Rui Song
{"title":"27-Hydroxycholesterol exacerbates hepatic insulin resistance via plasma membrane cholesterol remodeling","authors":"Jinni Yang , Xue Yang , Yuan Zheng , Anhui Wang , Ziwen Kong , Qinwen Xiao , Yuan Tian , Haijuan Dong , Zunjian Zhang , Min Wang , Rui Song","doi":"10.1016/j.metabol.2025.156392","DOIUrl":"10.1016/j.metabol.2025.156392","url":null,"abstract":"<div><h3>Background and aims</h3><div>Insulin resistance is a key driver of metabolic disorders, yet its molecular mechanisms remain elusive. This study identifies 27-hydroxycholesterol (27HC), a cholesterol-derived metabolite, and investigates its role in insulin resistance.</div></div><div><h3>Methods</h3><div>Targeted metabolomics quantified absolute and relative levels of 27HC (27HC/cholesterol ratio) in patients, mice, and hepatocytes. Insulin resistant mouse models were established to characterize spatiotemporal dynamics of 27HC and related enzymes. Functional analyses assessed 27HC's effect on insulin signaling across multiple hepatocyte types. Transcriptomic analysis identified key effector pathways. Plasma membrane cholesterol accessibility was evaluated using biosensors and validated by cholesterol rescue. Membrane protein extraction, immunofluorescence, and flow cytometry were employed to assess the impact of 27HC on insulin receptor (IR) distribution and binding capacity.</div></div><div><h3>Results</h3><div>Elevated 27HC levels were observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), obese and type 2 diabetic mice (T2DM), and PA-treated HepG2 and primary hepatocytes, correlating with impaired insulin sensitivity. CYP27A1 was identified as the key enzyme regulating liver 27HC levels. In vitro studies demonstrated that 27HC disrupts insulin signaling in HepG2, AML12, and primary hepatocytes, whereas CYP27A1 knockdown restored IR responsiveness. 27HC suppresses SREBP2-dependent cholesterol biosynthesis, depleting accessible cholesterol in the plasma membrane, triggering IR mislocalization and signal attenuation. Liver-specific CYP27A1 silencing in mice fed a high-fat diet improved systemic insulin sensitivity and restored metabolic homeostasis.</div></div><div><h3>Conclusion</h3><div>Our findings establish 27HC as a key effector linking cholesterol metabolism to insulin resistance and propose CYP27A1 inhibition as a potential therapeutic strategy for insulin resistance.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156392"},"PeriodicalIF":11.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081130","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}