Molecular Metabolism最新文献

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Kynurenic acid derived from mesentery regulates mesenteritis and colitis via inducing white adipose browning in Crohn’s disease 来源于肠系膜的犬尿酸通过诱导克罗恩病的白色脂肪褐变调节肠系膜炎和结肠炎。
IF 7 2区 医学
Molecular Metabolism Pub Date : 2025-07-05 DOI: 10.1016/j.molmet.2025.102203
Yongheng Wang , Ritian Lin , Fangtao Wang , Huijun Fu , Xia Wang , Fengshan Jin , Qiao Wang , Weigang Shu
{"title":"Kynurenic acid derived from mesentery regulates mesenteritis and colitis via inducing white adipose browning in Crohn’s disease","authors":"Yongheng Wang ,&nbsp;Ritian Lin ,&nbsp;Fangtao Wang ,&nbsp;Huijun Fu ,&nbsp;Xia Wang ,&nbsp;Fengshan Jin ,&nbsp;Qiao Wang ,&nbsp;Weigang Shu","doi":"10.1016/j.molmet.2025.102203","DOIUrl":"10.1016/j.molmet.2025.102203","url":null,"abstract":"<div><h3>Objective</h3><div>Hypertrophied mesenteric adipose tissue (MAT) wrapped around the inflamed intestine, also known as creeping fat (CrF), is a classic pathological characteristic of Crohn’s disease (CD). Recent studies revealed that the abnormal mesentery in CD exhibits a white-to-beige transformation (known as white adipose browning), which may be a compensatory mechanism for disease attenuation. However, its underlying causes and mechanisms remain unknown.</div></div><div><h3>Methods</h3><div>The beige MAT samples from patients with CD and normal white MAT samples from patients without CD were collected, and targeted metabolome analysis was performed. Interleukin-10 gene knockout <em>(IL-10</em><sup>−/−</sup><em>)</em> and 2,4,6-trinitrobenzenesulphonic acid solution (TNBS)-induced colitis mice were used to evaluate the effects of kynurenic acid (KYNA) on mesenteritis and colitis. Mesenteric explants and adipocytes were collected and cultured to assess the effects of KYNA on adipose tissue browning and macrophage inflammation.</div></div><div><h3>Results</h3><div>Targeted metabolomic sequencing revealed that KYNA exhibited the highest level of upregulation in the beige MAT of CD, which was tightly correlated with the browning marker UCP-1, inflammatory factors, and adipokines. <em>In vivo</em> experiments demonstrated that KYNA triggered the white-to-beige transformation of MAT in <em>IL-10</em><sup>−/−</sup> and TNBS-induced colitis mice, which further alleviated mesenteritis and colitis. Additionally, mesenteric explants and adipocytes displayed a browning phenotype with KYNA co-incubation, and their supernatants significantly induced M2 macrophage polarization and inhibited inflammation. Mechanistically, KYNA induced MAT browning and regulated disease procession of CD via GPR35-ERK1/2-PGC-1α signaling pathway.</div></div><div><h3>Conclusions</h3><div>This study provides novel insights into the browning transformation of the mesentery in CD and suggests a potential approach for clinical therapy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102203"},"PeriodicalIF":7.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584319","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}
引用次数: 0
Complete loss of PAX4 causes transient neonatal diabetes in humans PAX4基因的完全缺失导致人类新生儿短暂性糖尿病
IF 7 2区 医学
Molecular Metabolism Pub Date : 2025-07-02 DOI: 10.1016/j.molmet.2025.102201
James Russ-Silsby , Yunkyeong Lee , Varsha Rajesh , Mahsa Amoli , Nasser Ali Mirhosseini , Tushar Godbole , Matthew B. Johnson , D. Evelyn Ibarra , Han Sun , Nicole A.J. Krentz , Matthew N. Wakeling , Sarah E. Flanagan , Andrew T. Hattersley , Anna L. Gloyn , Elisa De Franco
{"title":"Complete loss of PAX4 causes transient neonatal diabetes in humans","authors":"James Russ-Silsby ,&nbsp;Yunkyeong Lee ,&nbsp;Varsha Rajesh ,&nbsp;Mahsa Amoli ,&nbsp;Nasser Ali Mirhosseini ,&nbsp;Tushar Godbole ,&nbsp;Matthew B. Johnson ,&nbsp;D. Evelyn Ibarra ,&nbsp;Han Sun ,&nbsp;Nicole A.J. Krentz ,&nbsp;Matthew N. Wakeling ,&nbsp;Sarah E. Flanagan ,&nbsp;Andrew T. Hattersley ,&nbsp;Anna L. Gloyn ,&nbsp;Elisa De Franco","doi":"10.1016/j.molmet.2025.102201","DOIUrl":"10.1016/j.molmet.2025.102201","url":null,"abstract":"<div><h3>Objective</h3><div>Gene discovery studies in individuals with diabetes diagnosed within 6 months of life (neonatal diabetes, NDM) can provide unique insights into the development and function of human pancreatic beta-cells.</div></div><div><h3>Methods</h3><div>We performed genome sequencing in a cohort of 43 consanguineous individuals with NDM in whom all the known genetic causes had previously been excluded. We used quantitative PCR and RNA-sequencing in CRISPR-edited human induced pluripotent stem cells (iPSCs), and CUT&amp;RUN-sequencing in EndoC-βH1 cells to investigate the effect of <em>PAX4</em> loss on human pancreatic development.</div></div><div><h3>Results</h3><div>We describe the identification of homozygous <em>PAX4</em> loss-of-function variants in 2 individuals with transient NDM: a p.(Arg126∗) stop-gain variant and a c.-352_104del deletion affecting the first 4 <em>PAX4</em> exons. We confirmed the p.(Arg126∗) variant causes nonsense mediated decay in CRISPR-edited iPSC-derived pancreatic endoderm cells. Integrated analysis of CUT&amp;RUN-sequencing in EndoC-βH1 cells and RNA-sequencing in <em>PAX4</em>-depleted islet stem cell models identified genes directly regulated by PAX4 involved in both pancreatic islet development and glucose-stimulated insulin secretion.</div></div><div><h3>Conclusion</h3><div>We report the first human cases of complete loss of <em>PAX4</em>, establishing it as a novel cause of NDM and highlighting its role in human beta cell development. Both probands had transient NDM which remitted in early infancy but relapsed at the ages of 2.4 and 6.7 years, demonstrating that in contrast to mouse models, PAX4 is not essential for the development of human pancreatic beta-cells.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102201"},"PeriodicalIF":7.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564953","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}
引用次数: 0
Inactivity-induced NR4A3 downregulation in human skeletal muscle affects glucose metabolism and translation: Insights from in vitro analysis 人体骨骼肌中不活动诱导的NR4A3下调影响葡萄糖代谢和翻译:来自体外分析的见解
IF 7 2区 医学
Molecular Metabolism Pub Date : 2025-07-01 DOI: 10.1016/j.molmet.2025.102200
Jonathon A.B. Smith , Brendan M. Gabriel , Aidan J. Brady , Ahmed M. Abdelmoez , Mladen Savikj , Shane C. Wright , Stefania Koutsilieri , Romain Barrès , Volker M. Lauschke , Anna Krook , Juleen R. Zierath , Nicolas J. Pillon
{"title":"Inactivity-induced NR4A3 downregulation in human skeletal muscle affects glucose metabolism and translation: Insights from in vitro analysis","authors":"Jonathon A.B. Smith ,&nbsp;Brendan M. Gabriel ,&nbsp;Aidan J. Brady ,&nbsp;Ahmed M. Abdelmoez ,&nbsp;Mladen Savikj ,&nbsp;Shane C. Wright ,&nbsp;Stefania Koutsilieri ,&nbsp;Romain Barrès ,&nbsp;Volker M. Lauschke ,&nbsp;Anna Krook ,&nbsp;Juleen R. Zierath ,&nbsp;Nicolas J. Pillon","doi":"10.1016/j.molmet.2025.102200","DOIUrl":"10.1016/j.molmet.2025.102200","url":null,"abstract":"<div><h3>Objective</h3><div>Physical activity promotes health, whereas inactivity is associated with metabolic impairment. The transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3) is a pleiotropic regulator of skeletal muscle exercise adaptation and metabolism. However, the consequence of lower NR4A3 expression remains largely unexplored. We investigated the impact of NR4A3 downregulation on human skeletal muscle metabolism.</div></div><div><h3>Methods</h3><div>Published transcriptomic datasets from human bed rest and limb immobilisation studies were curated to meta-analyse the effect of physical inactivity on skeletal muscle <em>NR4A3</em> levels. In primary human skeletal myotubes, siRNA and lentivirus were used to silence and overexpress <em>NR4A3</em>, respectively. Basal and stimulated (insulin ± leucine) signal transduction was determined by immunoblot analysis. Effects on glucose, fatty acid, and protein metabolism were measured using radiolabelled substrate assays. Lactate production was assessed in culture supernatant by colourimetry. Cell morphology was analysed by immunocytochemistry and gene expression was quantified by RT-qPCR.</div></div><div><h3>Results</h3><div>Physical inactivity decreased skeletal muscle <em>NR4A3</em> (−27%), concomitant with pathways related to mitochondrial function, cytoskeleton organization, chromatin regulation, protein synthesis and degradation. Silencing of <em>NR4A3</em> reduced glucose oxidation (−18%) and increased lactate production (+23%) <em>in vitro</em>. This coincided with greater signalling downstream of AMPK and elevated rates of basal (+26%) and FCCP-stimulated (+55%) fatty acid oxidation. NR4A3 downregulation lowered protein synthesis (−25%), and impaired mTORC1 signalling and ribosomal transcription. Alternatively, overexpression of the canonical NR4A3 protein isoform (+290%) augmented translation and total cellular protein content, which protected myotubes against dexamethasone-induced atrophy. Moreover, partial restoration of <em>NR4A3</em> levels rescued glucose oxidation in <em>NR4A</em><em>3</em>-silenced muscle cells and restored phosphorylation of mTORC1 substrates. NR4A3 depletion reduced myotube area (−48%) and further altered protein and gene expression of key contractile elements in skeletal muscle.</div></div><div><h3>Conclusions</h3><div>Our study connects reduced NR4A3 expression with physical inactivity and indicates that NR4A3 downregulation in human skeletal muscle has adverse effects on glucose metabolism and protein synthesis. Thus, decrements in NR4A3 abundance could be causal in the deleterious health consequences resulting from sedentary lifestyles and targeting NR4A3 may offer new avenues for combating conditions such as disuse muscle atrophy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102200"},"PeriodicalIF":7.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560532","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}
引用次数: 0
Dorsal raphe nucleus MC4R-GABAergic neurons regulate feeding and anxiety 中缝背核mc4r - gaba能神经元调节摄食和焦虑。
IF 7 2区 医学
Molecular Metabolism Pub Date : 2025-06-30 DOI: 10.1016/j.molmet.2025.102199
Satoshi Yamagata , Francesca Copperi , Gavin Thomas White , Jung Dae Kim , Sabrina Diano
{"title":"Dorsal raphe nucleus MC4R-GABAergic neurons regulate feeding and anxiety","authors":"Satoshi Yamagata ,&nbsp;Francesca Copperi ,&nbsp;Gavin Thomas White ,&nbsp;Jung Dae Kim ,&nbsp;Sabrina Diano","doi":"10.1016/j.molmet.2025.102199","DOIUrl":"10.1016/j.molmet.2025.102199","url":null,"abstract":"<div><h3>Objective</h3><div>The melanocortin receptor 4 (MC4R) plays a key role in the CNS regulation of metabolism. In addition to its role within the hypothalamus, other brain areas, including the dorsal raphe nucleus (DRN), express MC4R. However, the identity and role of these neurons in metabolism regulation are not fully understood. We performed studies to address these questions.</div></div><div><h3>Methods</h3><div>We generated <em>Mc4r-cre;Vgat-FlpO</em> and <em>Mc4r-cre;Vglut2-FlpO</em> mice to determine the contribution of these MC4R neuronal populations in DRN. We then chemogenetically activated or inhibited the GABAergic and glutamatergic populations of MC4R. Finally, we selectively deleted MC4R from these two neuronal populations and studied the impact on whole-body metabolism.</div></div><div><h3>Results</h3><div>We found that about 60% of DRN MC4R neurons are GABAergic (Vgat), while only about 20% are glutamatergic (Vglut2). Most of the projections onto DRN neurons originated from the arcuate nucleus (ARC)-POMC neurons, and only a small input from the nucleus of the solitary tract (NTS)-POMC neurons was identified. Significant projections of DRN MC4R/Vgat neurons were observed in the paraventricular nucleus of the hypothalamus (PVN). Chemogenetic activation or inhibition of MC4R/Vgat neurons increased or inhibited food intake, respectively. No effects were observed when the same approach was used in MC4R/Vglut2 neurons. Furthermore, only chemogenetic manipulation of the MC4R/Vgat neurons affected anxiety-like behavior, which was associated with changes in serotonin staining in the DRN. Finally, MC4R-selective deletion in Vgat but not Vglut2 neurons affected whole-body metabolism.</div></div><div><h3>Conclusions</h3><div>These findings suggest that DRN MC4R/Vgat neurons receiving projections from the ARC POMC neurons and projecting to the hypothalamic PVN play a role in metabolism regulation. In addition, this same DRN neuronal subpopulation affects anxiety-like behavior by modulating DRN serotonin neurons.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102199"},"PeriodicalIF":7.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553993","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}
引用次数: 0
An epigenome atlas of mouse adipocytes 小鼠脂肪细胞表观基因组图谱。
IF 7 2区 医学
Molecular Metabolism Pub Date : 2025-06-27 DOI: 10.1016/j.molmet.2025.102197
Laura C. Hinte , Adhideb Ghosh , Daniel Castellano-Castillo , Christian Wolfrum , Ferdinand von Meyenn
{"title":"An epigenome atlas of mouse adipocytes","authors":"Laura C. Hinte ,&nbsp;Adhideb Ghosh ,&nbsp;Daniel Castellano-Castillo ,&nbsp;Christian Wolfrum ,&nbsp;Ferdinand von Meyenn","doi":"10.1016/j.molmet.2025.102197","DOIUrl":"10.1016/j.molmet.2025.102197","url":null,"abstract":"<div><h3>Objective</h3><div>Epigenetic modifications including histone post translational modifications can influence gene expression in adipocytes, potentially contributing to metabolic dysfunctions, obesity, and insulin resistance. Despite recent advances in the characterization of the mouse adipocyte epigenome, epigenetic characterization of adipocytes <em>in vivo</em> has been challenging, particularly across different adipose depots and of several epigenetic modifications.</div></div><div><h3>Methods</h3><div>Here, we use specific reporter mice labelling brown, beige and white adipocytes, diphtheria toxin-mediated ablation of beige adipocytes, and Cleavage Under Targets and Tagmentation (CUT&amp;Tag) to generate paired single mouse datasets of five histone marks. We perform an integrative multi-omics factor analysis (MOFA) of H3K4me3, H3K27me3, H3K4me1, H3K27ac and H3K9me3 in brown, white and beige adipocytes from three distinct mouse adipose tissue depots obtained during cold exposure and thermoneutrality.</div></div><div><h3>Results</h3><div>Our analysis reveals that enhancers distinguish adipocytes by their tissue of origin, with H3K4me1 deposition differentiating between beige and brown adipocytes. Beige adipocytes poised promoters associated to thermogenic genes during warming. Diphtheria toxin-mediated ablation of beige adipocytes shows that non-beigeing white adipocytes in inguinal adipose tissue and beige adipocytes are not inherently epigenetically different suggesting that they share a common developmental progenitor.</div></div><div><h3>Conclusions</h3><div>These paired multimodal data comprise an extensive resource (<span><span>https://github.com/vonMeyennLab/mAT_CE_Atlas</span><svg><path></path></svg></span>) for the further exploration of the mouse adipocyte epigenome which will enable discovery of regulatory elements governing adipocyte identity and gene regulation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102197"},"PeriodicalIF":7.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528836","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}
引用次数: 0
Adropin expression reflects circadian, lipoprotein, and mitochondrial processes in human tissues Adropin的表达反映了人体组织中的昼夜节律、脂蛋白和线粒体过程。
IF 7 2区 医学
Molecular Metabolism Pub Date : 2025-06-26 DOI: 10.1016/j.molmet.2025.102196
Joseph R. Stevens , Clemence Girardet , Mingqi Zhou , Farah Gamie , Geetika Aggarwal , Ryan P. McMillan , Matthew W. Hulver , Laurent O. Martinez , Marcel van der Brug , Bruno Vellas , Andrew D. Nguyen , Marcus M. Seldin , Andrew A. Butler
{"title":"Adropin expression reflects circadian, lipoprotein, and mitochondrial processes in human tissues","authors":"Joseph R. Stevens ,&nbsp;Clemence Girardet ,&nbsp;Mingqi Zhou ,&nbsp;Farah Gamie ,&nbsp;Geetika Aggarwal ,&nbsp;Ryan P. McMillan ,&nbsp;Matthew W. Hulver ,&nbsp;Laurent O. Martinez ,&nbsp;Marcel van der Brug ,&nbsp;Bruno Vellas ,&nbsp;Andrew D. Nguyen ,&nbsp;Marcus M. Seldin ,&nbsp;Andrew A. Butler","doi":"10.1016/j.molmet.2025.102196","DOIUrl":"10.1016/j.molmet.2025.102196","url":null,"abstract":"<div><div>The clinical significance of interindividual variation in circulating adropin levels is unclear. To better understand adropin biology at the whole-body level, we surveyed transcriptional structures co-regulated with the Energy Homeostasis Associated (<em>ENHO</em>) gene encoding adropin across human tissues using Gene-Derived Correlations Across Tissues (GD-CAT). <em>ENHO</em>/adropin-related transcriptional structures with &gt;1000 genes meeting the selection threshold (q &lt; 0.001) occurred in 11/20 tissues. While most reflect local relationships, liver <em>ENHO</em>/adropin-related structures are dominated by transcripts expressed across metabolic tissues (skeletal muscle, adipose tissues, thyroid). Relationships between liver <em>ENHO</em>/adropin expression and skeletal muscle mitochondrial function were corroborated using liver-specific knockout mice. Within-liver <em>ENHO</em>/adropin transcriptional structures reflect lipoprotein metabolism (e.g., <em>APOC1</em>, p = 4.91 x 10<sup>−11</sup>; <em>APOA1</em>, p = 8.03 x 10<sup>−9</sup>), confirmed by correlations between plasma concentrations of adropin and indices of lipoprotein metabolism in MAPT samples. Moreover, statin treatment which increases hepatic cholesterol efflux, reduces plasma adropin levels. The <em>ENHO</em> gene contains retinoic acid receptor-related orphan receptor response elements (RORE), suggesting circadian control. Pan-organ transcriptional structures with liver <em>ENHO</em>/adropin or <em>RORC</em> overlap, reflecting the liver clock. Strong, local relationships between <em>ENHO</em>/adropin and circadian genes were also observed in most non-hepatic tissues. <em>ENHO</em>/adropin expression widely reflects activation of oxidative metabolic pathways and suppression of ribosomal functions and cell division. Finally, hippocampal <em>ENHO</em>/adropin expression correlates strongly with Alzheimer's disease risk genes identified by GWAS. In summary, activation of <em>ENHO</em>/adropin expression reflects cellular circadian and mitochondrial oxidative processes, but with inhibition of anabolic processes. Plasma adropin concentrations may thus reflect hepatic lipoprotein production and activation of metabolic stress responses across human tissues.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102196"},"PeriodicalIF":7.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512208","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}
引用次数: 0
Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection 急性和慢性淋巴细胞性脉络丛脑膜炎病毒感染的全身代谢变化。
IF 7 2区 医学
Molecular Metabolism Pub Date : 2025-06-26 DOI: 10.1016/j.molmet.2025.102194
Caroline R. Bartman , Shengqi Hou , Fabian Correa , Yihui Shen , Victoria da Silva-Diz , Maya Aleksandrova , Daniel Herranz , Joshua D. Rabinowitz , Andrew M. Intlekofer
{"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}
引用次数: 0
Subtyping of type 2 diabetes from a large Middle Eastern biobank: Implications for precision medicine 来自中东大型生物库的2型糖尿病亚型:对精准医学的影响。
IF 7 2区 医学
Molecular Metabolism Pub Date : 2025-06-23 DOI: 10.1016/j.molmet.2025.102195
Nayra M. Al-Thani , Shaza B. Zaghlool , Salman M. Toor , Abdul Badi Abou-Samra , Karsten Suhre , Omar M.E. Albagha
{"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}
引用次数: 0
Creatine kinase B mediates UCP1-independent beige fat thermogenesis via the futile creatine cycle in mice 肌酸激酶B介导小鼠不依赖于ucp1的米色脂肪产热。
IF 7 2区 医学
Molecular Metabolism Pub Date : 2025-06-23 DOI: 10.1016/j.molmet.2025.102193
Jakub Bunk , Mina Ersin , Mohammed F. Hussain , Bozena Samborska , Maria Guerra-Martinez , Drishti Soni , Lawrence Kazak
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引用次数: 0
Metabolic consequences of altered kidney glucose reabsorption under normoglycemic conditions 正常血糖条件下肾脏葡萄糖重吸收改变的代谢后果。
IF 7 2区 医学
Molecular Metabolism Pub Date : 2025-06-21 DOI: 10.1016/j.molmet.2025.102192
Majdoleen Ahmad , Anna Permyakova , Saja Baraghithy , Nilanjan Sahu , Ifat Abramovich , Bella Agranovich , Ori Shalev , Aviram Kogot-Levin , Alina Nemirovski , Eyal Gottlieb , Rinat Abramovitch , Gil Leibowitz , Liad Hinden , Joseph Tam
{"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}
引用次数: 0
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