Molecular Metabolism最新文献

{"title":"Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection","authors":"Caroline R. Bartman ,&nbsp;Shengqi Hou ,&nbsp;Fabian Correa ,&nbsp;Yihui Shen ,&nbsp;Victoria da Silva-Diz ,&nbsp;Maya Aleksandrova ,&nbsp;Daniel Herranz ,&nbsp;Joshua D. Rabinowitz ,&nbsp;Andrew M. Intlekofer","doi":"10.1016/j.molmet.2025.102194","DOIUrl":"10.1016/j.molmet.2025.102194","url":null,"abstract":"<div><h3>Objective</h3><div>Viral infection of cells leads to metabolic changes, but how viral infection changes whole-body and tissue metabolism <em>in vivo</em> has not been comprehensively studied. In particular, it is unknown how metabolism might be differentially affected by an acute infection that the immune system can successfully clear compared to a chronic persistent infection.</div></div><div><h3>Methods</h3><div>Here we used metabolomics and isotope tracing to identify metabolic changes in mice infected with acute or chronic forms of lymphocytic choriomeningitis virus (LCMV) for three or eight days.</div></div><div><h3>Results</h3><div>Both types of infection alter metabolite levels in blood and tissues, including itaconate and thymidine. However, we observed more dramatic metabolite changes in the blood and tissues of mice with persisting LCMV infection compared to those infected with the acute viral strain. Isotope tracing revealed that the contribution of both glucose and glutamine to the tricarboxylic acid (TCA) cycle increase in the spleen, liver, and kidneys of mice infected with chronic LCMV, while acute LCMV only increases the contribution of glutamine to the TCA cycle in the spleen. We found that whole-body turnover of both glutamine and thymidine increase during acute and chronic infection, whereas whole-body glucose turnover surprisingly does not change. Activated T cells <em>in vitro</em> produce thymidine and virus-specific T cells <em>ex vivo</em> have increased thymidine levels, nominating T lymphocytes as the source of thymidine in LCMV infection.</div></div><div><h3>Conclusions</h3><div>In sum, we provide comprehensive measurements of whole-body and tissue metabolism in acute and chronic viral infection, and identify altered thymidine metabolism as a marker of viral infection.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102194"},"PeriodicalIF":7.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528837","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":"Subtyping of type 2 diabetes from a large Middle Eastern biobank: Implications for precision medicine","authors":"Nayra M. Al-Thani ,&nbsp;Shaza B. Zaghlool ,&nbsp;Salman M. Toor ,&nbsp;Abdul Badi Abou-Samra ,&nbsp;Karsten Suhre ,&nbsp;Omar M.E. Albagha","doi":"10.1016/j.molmet.2025.102195","DOIUrl":"10.1016/j.molmet.2025.102195","url":null,"abstract":"<div><div>Type 2 diabetes (T2D) can be classified into Severe Insulin-Deficient Diabetes (SIDD), Severe Insulin-Resistant Diabetes (SIRD), Mild Obesity-related Diabetes (MOD), and Mild Age-related Diabetes (MARD). This classification can help in predicting disease complications and determining the best treatment for individuals. However, the applicability of this classification to non-European populations and sensitivity to confounding factors remain unclear. We applied k-means clustering to a large Middle Eastern biobank cohort (Qatar Biobank; QBB, comprising 13,808 individuals; 2,687 with T2D). We evaluated the efficacy of the European cluster coordinates and analyzed the impact of using actual age on clustering outcomes. We examined sex differences, analyzed insulin treatment frequency, investigated the clustering of monogenic diabetes (MD) focusing on maturity-onset diabetes of the young (MODY), and evaluated the prevalence of chronic kidney disease (CKD) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) among T2D subtypes. We identified the four T2D subtypes within a large Arab cohort. Data-derived centers outperformed European coordinates in classifying T2D. The use of actual age, as opposed to age of diagnosis, impacted MOD and MARD classification. Obesity prevalence was significantly higher in females but it did not translate to worse disease severity, as indicated by comparable levels of HbA1C and HOMA2-IR. Insulin was predominantly prescribed to individuals in SIDD and SIRD. SIRD displayed the highest risk of CKD and MASLD, followed by MOD and SIDD compared to MARD. Interestingly, most MODY individuals were clustered within MARD, further highlighting the need for precise classification and tailored interventions. The observed sex differences underscore the importance of tailoring treatment plans for females compared to males. Individuals who are at a higher risk of CKD and MASLD may require closer monitoring and physician oversight. Additionally, in populations without access to genetic testing, likely MODY individuals can be identified within the MARD cluster. Our findings strongly support the need for a transition to more personalized, data-driven treatment approaches to minimize diabetes-related complications and improve disease outcomes.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102195"},"PeriodicalIF":7.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497507","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":"Creatine kinase B mediates UCP1-independent beige fat thermogenesis via the futile creatine cycle in mice","authors":"Jakub Bunk ,&nbsp;Mina Ersin ,&nbsp;Mohammed F. Hussain ,&nbsp;Bozena Samborska ,&nbsp;Maria Guerra-Martinez ,&nbsp;Drishti Soni ,&nbsp;Lawrence Kazak","doi":"10.1016/j.molmet.2025.102193","DOIUrl":"10.1016/j.molmet.2025.102193","url":null,"abstract":"<div><h3>Objectives</h3><div>Creatine kinase B (CKB) is the main isoenzyme driving creatine kinase (CK) activity in classical brown adipocytes. However, the specific CK isoenzyme active in beige adipocytes remains unknown. This study aimed to identify the predominant CK isoenzyme expressed and functionally active in beige adipocytes.</div></div><div><h3>Methods</h3><div>CK activity was tracked using D3-creatine tracing in inguinal adipocytes from mice with adipocyte-specific <em>Ckb</em> deletion and their littermate controls, across <em>in vivo</em> and <em>in vitro</em> settings.</div></div><div><h3>Results</h3><div>CKB was essential for CK activity in protein lysates and intact white and beige adipocytes isolated from inguinal fat and drives thermogenesis through the Futile Creatine Cycle.</div></div><div><h3>Conclusions</h3><div>Similar to classical brown adipocytes, CKB is the key functional CK isoenzyme in white and beige adipocytes from the inguinal fat depot.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102193"},"PeriodicalIF":7.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497506","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":"Metabolic consequences of altered kidney glucose reabsorption under normoglycemic conditions","authors":"Majdoleen Ahmad ,&nbsp;Anna Permyakova ,&nbsp;Saja Baraghithy ,&nbsp;Nilanjan Sahu ,&nbsp;Ifat Abramovich ,&nbsp;Bella Agranovich ,&nbsp;Ori Shalev ,&nbsp;Aviram Kogot-Levin ,&nbsp;Alina Nemirovski ,&nbsp;Eyal Gottlieb ,&nbsp;Rinat Abramovitch ,&nbsp;Gil Leibowitz ,&nbsp;Liad Hinden ,&nbsp;Joseph Tam","doi":"10.1016/j.molmet.2025.102192","DOIUrl":"10.1016/j.molmet.2025.102192","url":null,"abstract":"<div><h3>Objective</h3><div>Kidney glucose reabsorption, primarily mediated by glucose transporter 2 (GLUT2), is essential for systemic glucose homeostasis. While GLUT2's role has been studied in diabetic conditions, its function in kidney proximal tubule cells (KPTCs) under normo-physiological conditions remains unclear. This study aimed to delineate the metabolic consequences of KPTC-specific GLUT2 deletion on renal and whole-body energy homeostasis.</div></div><div><h3>Methods</h3><div>We utilized a conditional mouse model with KPTC-specific deletion of GLUT2 to assess the impact of impaired renal glucose reabsorption on systemic metabolism. Comprehensive metabolic and behavioral phenotyping, tissue-specific glucose uptake assays, and multi-omics analyses were performed to evaluate changes in energy balance, organ-specific metabolism, and signaling pathways.</div></div><div><h3>Results</h3><div>Loss of KPTC-GLUT2 led to increased food intake, enhanced systemic carbohydrate oxidation, and elevated fat and muscle mass. These changes were accompanied by altered glucose utilization across metabolic organs and improvements in whole-body lipid profile. Mechanistically, the phenotype was linked to metabolic reprogramming in the kidney, characterized by increased reabsorption and bioavailability of taurine and creatine, overactivation of mTORC1 signaling, and elevated endocannabinoid tone.</div></div><div><h3>Conclusions</h3><div>KPTC-GLUT2 plays a previously unrecognized role in regulating renal and systemic energy metabolism. Its deletion induces a systemic energy-conserving phenotype driven by kidney-intrinsic changes, highlighting the kidney's contribution to whole-body metabolic homeostasis beyond glucose filtration.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102192"},"PeriodicalIF":7.0,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476056","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":"Creatinine promotes adipose tissue wasting in chronic kidney disease via creatine and futile creatine cycle","authors":"Jingwen Fang ,&nbsp;Xianfen Huang ,&nbsp;Chanchan Guo ,&nbsp;Ting Chen ,&nbsp;Yubing Chen ,&nbsp;Xiaobing Yang ,&nbsp;Min Zheng ,&nbsp;Hanying Ding","doi":"10.1016/j.molmet.2025.102191","DOIUrl":"10.1016/j.molmet.2025.102191","url":null,"abstract":"<div><h3>Objective</h3><div>Cachexia in chronic kidney disease (CKD) is a wasting syndrome. The futile creatine cycle (FCC) contributes to energy waste in adipocytes. Creatinine is metabolite of creatine. Whether creatinine involves in adipose wasting in CKD remains elusive.</div></div><div><h3>Methods</h3><div>Cachexia were assessed in unilateral ureteral obstruction induced CKD mice model. Cellular oxygen consumption and FCC-related genes expression were analyzed in adipocytes treated with creatinine in the presence of FCC inhibitor (SBI-425, inhibitor of TNAP) or creatine disruption (β-GPA, a creatine analogue that inhibits creatine transport into cells). The fate of labeled deuterated creatinine (D-3 creatinine) were traced by mass spectrometer. To determine creatinine drives adipose tissue wasting <em>in vivo</em>, two mice models of CKD were established by unilateral ureteral obstruction or renal ischemia and reperfusion injury. 206 patients diagnosed CKD were collected to analyze correlationship between creatinine in serum and adiposity.</div></div><div><h3>Results</h3><div>Adipose tissue wasting presented in CKD mice with serumal creatinine retention. <em>In vitro,</em> creatinine treatment at the concentration relevant of CKD elevated cellular oxygen consumption and FCC-related genes expression by converting into intracellular creatine. In the established CKD mice models, intraperitoneal injection of creatinine enhanced adipose tissue wasting, through increasing creatine accumulation. In contrast, disruption of creatine accumulation by β-GPA ameliorated tissue wasting. In patients with CKD, creatinine in serum negatively correlated with adiposity.</div></div><div><h3>Conclusions</h3><div>Our results show that elevated serumal creatinine induces creatine accumulation, FCC activation and adipose tissue wasting in CKD, targeting creatinine-induced tissue wasting providing a promising therapeutic to ameliorate cachexia in CKD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102191"},"PeriodicalIF":7.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340271","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":"Fatty Acid Synthase regulates glucose and energy homeostasis via POMC neurons and adrenergic signals","authors":"Luis Leon-Mercado ,&nbsp;Yanbin Dong ,&nbsp;Bandy Chen ,&nbsp;Arely Tinajero ,&nbsp;Caleb C. Lord ,&nbsp;Syann Lee ,&nbsp;Chen Liu ,&nbsp;Guosheng Liang ,&nbsp;Jay D. Horton ,&nbsp;Kevin W. Williams ,&nbsp;Joel K. Elmquist","doi":"10.1016/j.molmet.2025.102177","DOIUrl":"10.1016/j.molmet.2025.102177","url":null,"abstract":"<div><h3>Objectives</h3><div>Hypothalamic Fatty Acid Synthase (FASN) plays a critical role in regulating energy balance by influencing food intake and body weight. This study aimed to investigate the neuronal mechanisms by which FASN impacts metabolism, focusing on its role in Pro-Opiomelanocortin (POMC) neurons.</div></div><div><h3>Methods</h3><div>We used transgenic mouse models with pre- or postnatal deletion of FASN specifically in POMC neurons in male mice. We evaluated changes in adiposity, glucose metabolism and metabolic parameters including food intake, energy expenditure and substrate utilization using metabolic chambers. Changes in neuronal activity were assessed using electrophysiology and further validated by optogenetic stimulation of POMC neurons. Additionally, the role of adrenergic signaling was examined using pharmacological approaches and gene expression analyses.</div></div><div><h3>Results</h3><div>FASN deletion in POMC neurons reduced food intake, decreased adiposity, and altered glucose metabolism. FASN-deficient POMC neurons exhibited increased baseline activity. The developmental stage of FASN deletion influenced its effects on energy expenditure and body weight regulation. Additionally, FASN in POMC neurons was found to be essential for maintaining glucose homeostasis and insulin release via adrenergic signaling.</div></div><div><h3>Conclusions</h3><div>FASN in POMC neurons plays an age- and neuron-specific role in regulating feeding, energy expenditure, and glucose homeostasis through mechanisms including the sympathetic nervous system. These findings highlight FASN as a potential therapeutic target for metabolic diseases by improving energy expenditure and insulinemia. Given the developmental programming of metabolic outcomes, interventions aimed at modulating FASN activity may have long-lasting benefits in managing metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102177"},"PeriodicalIF":7.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336748","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":"Housing matters: Experimental variables shaping metabolism in obese mice","authors":"Béatrice So-Yun Choi ,&nbsp;Jacob Bak Holm ,&nbsp;Asker Brejnrod ,&nbsp;Even Fjære ,&nbsp;Zhongkui Xia ,&nbsp;Marie-Louise Allingbjerg ,&nbsp;Ida Søgaard Larsen ,&nbsp;David Møbjerg Kristensen ,&nbsp;Morten Dall ,&nbsp;Lene Secher Myrmel ,&nbsp;Janne Koch ,&nbsp;Niels Banhos Danneskiold-Samsøe ,&nbsp;Otto Kalliokoski ,&nbsp;Jonas T. Treebak ,&nbsp;Liang Xiao ,&nbsp;Axel Kornerup Hansen ,&nbsp;Helle Sørensen ,&nbsp;Lise Madsen ,&nbsp;Manimozhiyan Arumugam ,&nbsp;Karsten Kristiansen ,&nbsp;Benjamin A.H. Jensen","doi":"10.1016/j.molmet.2025.102190","DOIUrl":"10.1016/j.molmet.2025.102190","url":null,"abstract":"<div><div>Diet-induced obesity in mice is an important model for investigating host–diet interactions as well as dietary and pharmacological treatments of metabolic diseases. Experimental reproducibility is, however, a recurrent challenge. To determine key controllable experimental drivers of mouse metabolism, we distributed 338C57BL/6JBomTac mice (males and females) into six research units across two countries, divided them into a variety of housing conditions (i.e., diets, cage types, temperatures, group-housing vs. single-housing) and kept 26 reference mice at the vendor. We applied linear mixed models to rank the influence of each variable on metabolic phenotype (i.e., body weight gain, glucose intolerance, liver, and visceral adipose tissue weight). Group-housing was the most potent driver of metabolic dysfunction apart from sex and diet. Accordingly, single-housed mice exhibited reduced weight gain (∼50%), increased energy expenditure, and diminished respiratory exchange ratio concomitant with improved glucose tolerance (∼20%) compared to their group-housed counterparts. Our results may aid in clarifying the impact of experimental design and promote rational, transparent reporting to increase reproducibility.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102190"},"PeriodicalIF":7.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485132","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":"Sex hormone-binding globulin controls sex-specific lipolytic activity in human abdominal subcutaneous adipocytes","authors":"Julie Abildgaard ,&nbsp;Aiste Aleliunaite ,&nbsp;Carla Horvath ,&nbsp;Nagendra Palani ,&nbsp;Tora Ida Henriksen ,&nbsp;Jiawei Zhong ,&nbsp;Katja Munch Lorentsen ,&nbsp;Victor Svenstrup ,&nbsp;Hanne Frederiksen ,&nbsp;Anders Juul ,&nbsp;Camilla Charlotte Scheele ,&nbsp;Søren Nielsen","doi":"10.1016/j.molmet.2025.102189","DOIUrl":"10.1016/j.molmet.2025.102189","url":null,"abstract":"<div><div>Regulation of lipid metabolism is fundamental for metabolic health, and adipose tissue is a central component in this process. Adipose tissue differs considerably between women and men in terms of a higher subcutaneous capacity for storage, which is linked to metabolic health, in women. Sex hormone-binding globulin (SHBG) contributes to the regulation of circulating sex hormone bioavailability and has been shown to predict risk of metabolic dysfunction. Here, we investigate the sex-specific relationship of SHBG with metabolic status and adipocyte-dependent lipolysis. We measured serum concentrations of sex hormones, SHBG, fasting glucose, and insulin in a cohort of 63 women and 27 men from which adipose biopsies were collected and mature adipocytes isolated. In women, high serum SHBG concentrations were strongly associated with low <em>in vivo</em> Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and lower unstimulated <em>ex vivo</em> lipolysis but higher isoprenaline stimulated <em>ex vivo</em> lipolysis. In contrast, no effect of SHBG on the above-mentioned parameters were observed in men. In vitro cultured human adipocytes also increased lipolytic activity in response to SHBG, but only in the absence of testosterone, suggesting that testosterone inhibits the catecholamine-induced lipolysis of SHBG in adipose tissue. In conclusion, we identify SHBG as a novel sex-specific regulator of adipocyte lipolysis and lipid metabolism. At the same time, our data emphasize sex-dependent effects of SHBG on adipocyte lipid metabolism, and we propose testosterone binding to SHBG as a driving factor mediating these sex differences.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102189"},"PeriodicalIF":7.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326226","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":"Sex differences in resting skeletal muscle and the acute and long-term response to endurance exercise in individuals with overweight and obesity","authors":"Simon I. Dreher ,&nbsp;Thomas Goj ,&nbsp;Christine von Toerne ,&nbsp;Miriam Hoene ,&nbsp;Martin Irmler ,&nbsp;Meriem Ouni ,&nbsp;Markus Jähnert ,&nbsp;Johannes Beckers ,&nbsp;Martin Hrabě de Angelis ,&nbsp;Andreas Peter ,&nbsp;Anja Moller ,&nbsp;Andreas L. Birkenfeld ,&nbsp;Annette Schürmann ,&nbsp;Stefanie M. Hauck ,&nbsp;Cora Weigert","doi":"10.1016/j.molmet.2025.102185","DOIUrl":"10.1016/j.molmet.2025.102185","url":null,"abstract":"<div><h3>Objectives</h3><div>Endurance exercise reduces the risk of metabolic diseases by improving skeletal muscle metabolism, particularly in individuals with overweight and obesity. As biological sex impacts glucose and fatty acid handling in skeletal muscle, we hypothesized sex differences at the transcriptomic and proteomic level in the acute response to exercise and after an 8-week exercise intervention.</div></div><div><h3>Methods</h3><div>We analyzed skeletal muscle biopsies from 25 sedentary subjects (16f/9 m) with overweight and obesity using transcriptomics and proteomics at baseline, after acute exercise, and following an 8-week endurance training program. Regulation of sex-specific differences was studied in primary myotubes from the donors.</div></div><div><h3>Results</h3><div>At baseline, differentially methylated CpG-sites potentially explain up to 59% of transcriptomic and 67% of proteomic sex differences. Differences were dominated by higher abundance of fast-twitch fiber type proteins, and transcripts and proteins regulating glycogen degradation and glycolysis in males. Females showed higher abundance of proteins regulating fatty acid uptake and storage. Acute exercise induced stress-responsive transcripts and serum myoglobin predominantly in males. Both sexes adapted to 8-week endurance training by upregulating mitochondrial proteins involved in TCA cycle, oxidative phosphorylation, and β-oxidation. Training equalized fast-twitch fiber type protein levels, mainly by reducing them in males. In vivo sex differences in autosomal genes were poorly retained in myotubes but partially restored by sex hormone treatment.</div></div><div><h3>Conclusions</h3><div>Our findings highlight sex-specific molecular signatures that reflect known differences in glucose and lipid metabolism between female and male skeletal muscle. After just 8 weeks of endurance training, these sex differences were attenuated, suggesting a convergence towards a shared beneficial adaptation at the molecular level.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102185"},"PeriodicalIF":7.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294119","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":"Isolation of live human δ cells for genetic and functional analysis","authors":"Yan Hang ,&nbsp;Mario Alex Miranda ,&nbsp;Ziqiao Yan ,&nbsp;Weichen Zhao ,&nbsp;Seung K. Kim","doi":"10.1016/j.molmet.2025.102188","DOIUrl":"10.1016/j.molmet.2025.102188","url":null,"abstract":"<div><div>Investigations of human pancreatic islets have been empowered by strategies to isolate and study live islet cell subsets, like β cells and α cells. To advance experimentation with human islet δ cells, which remain relatively understudied, we generated combinatorial cell sorting approaches to separate human δ cells from β cells, yielding highly-enriched human δ cells. We used molecular analysis, immunohistology, and electroporation-based targeting to demonstrate the quality of δ cell purification. We also demonstrated the feasibility of prospectively studying human δ cell function in pseudoislet organoids. Innovations detailed here should promote discovery of genetic, signaling and physiological mechanisms governing δ cell function and roles in human islets.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102188"},"PeriodicalIF":7.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294118","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}