npj Metabolic Health and Disease最新文献

{"title":"Dual SGLT1/2 inhibition with sotagliflozin improves cardiac function and metabolism in type 2 diabetic mice.","authors":"Megan Young, Sanushi Dambure, Fenn Cullen, Kimia Jarrah, Lana McClements, Zenouska Ramchunder, Dunja Aksentijevic","doi":"10.1038/s44324-026-00119-z","DOIUrl":"10.1038/s44324-026-00119-z","url":null,"abstract":"<p><p>Sotagliflozin (SOTA), a dual sodium-glucose cotransporter (SGLT)1/2 inhibitor, improves cardiovascular outcomes in patients with diabetes and heart failure, yet the metabolic mechanisms underlying these benefits remain incompletely defined. As a model of type 2 diabetes, db/db mice were treated with SOTA (5 mg/kg/day) in drinking water for 4 weeks. Cardiac metabolism was assessed using LC-MS/MS, cardiac function by echocardiography, and susceptibility to ischemia/reperfusion injury in Langendorff-perfused hearts. Systemic metabolism was characterised by plasma biochemical profiling and ¹H NMR spectroscopy of peripheral tissues. db/db mice exhibited obesity, hyperglycaemia, hyperinsulinaemia, and diastolic dysfunction, alongside perturbed cardiac and systemic metabolism. SOTA treatment improved hyperglycaemia, ventricular function and cardiac metabolomic profile without correcting obesity or insulin resistance. In the heart, SOTA partially restored glycolytic intermediates and improved bioenergetics, whereas systemic metabolic abnormalities largely persisted. These findings suggest dual SGLT1/2 inhibition induces selective cardiac metabolic remodelling in diabetic cardiomyopathy independent of global metabolic correction.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13443782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148681838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Life's crucial 9, plasma proteomics, and the risk of major complications and mortality in MASLD.","authors":"Bing-Yun Zhang, Yi-Xin Wang, Hong-Xuan Huang, Xu-Lian Tang, Shu-Min Lai, Zhi-Yuan Xiong, Ling Kuang, Hao-Jie Chen, Hui Zhu, Ya-Xuan Li, Si-Qi Chen, Er-La Huang, Yan-Song Li, Hai-Ying Wang, Junguo Zhang, Zhi-Hao Li","doi":"10.1038/s44324-026-00124-2","DOIUrl":"10.1038/s44324-026-00124-2","url":null,"abstract":"<p><p>Metabolically dysfunction-associated steatotic liver disease (MASLD) constitutes a major health burden. Whether a multidomain profile of modifiable health, as captured by Life's Crucial 9 (LC9), is associated with major complications in MASLD, and which plasma proteins underlie these associations, remains unclear. We evaluated LC9 in 59,433 individuals with MASLD, including 6,354 with plasma proteomic data. During a median follow-up of 13.8 years, participants in the highest versus lowest LC9 tertile had lower risks of major adverse cardiovascular events (HR 0.62), major adverse liver outcomes (HR 0.62), chronic kidney disease (HR 0.54), chronic respiratory disease (HR 0.63), all-cause mortality (HR 0.67), and cardiovascular mortality (HR 0.55). LC9 modestly improved discrimination for incident complications, but not materially for mortality. Proteomic analyses identified candidate mediators shared across outcomes, including FABP4 and HAVCR1. Our findings suggest LC9 provides a multidomain framework for MASLD risk stratification, offering candidate protein signatures for future mechanistic evaluation.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13434568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148671935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overweight and obesity induce Toll-like receptor 2-induced Type I IFN signaling.","authors":"Megan Elkins, Amer Al-Musa, Marcos Chiñas, Brian Woods, Aleksandra Bourdine, Lena Ludwig-Radtke, Brenna LaBere, Saddiq Habiballah, Alan A Nguyen, Toshiro K Ohsumi, Maria Gutierrez-Arcelus, Amy Fleischman, Verena Taudte, Janet Chou","doi":"10.1038/s44324-026-00125-1","DOIUrl":"10.1038/s44324-026-00125-1","url":null,"abstract":"<p><p>Toll-like receptor 2 (TLR2) is an innate immune receptor linked to obesity primarily via NF-κB activation. Using a mouse model of overnutrition and in vitro TLR2 stimulation of human peripheral blood mononuclear cells, we show that lipids, advanced glycation end products, and low-density lipoproteins extend TLR2 signaling beyond NF-κB to promote Type I IFN production and signaling, establishing the relevance of this pathway to human obesity. This response was abolished by pharmacologic inhibition of the receptor for advanced glycation end products, which recognizes glycated proteins and lipids. In vivo dietary reversal, metformin, and tirzepatide each reduced diet-induced inflammation, but differed in their metabolic effects: dietary reversal reduced weight gain and LDL, tirzepatide reduced weight without lowering LDL, and metformin exerted anti-inflammatory effects independent of weight or LDL. These findings identify TLR2-Type I IFN signaling as a feature of diet-induced inflammation and highlight the diverse immunomodulatory effects of weight-management therapies.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13434816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148671922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding regional differences in MASLD: the Indian perspective.","authors":"Karthik Shree Harini, Devaraj Ezhilarasan","doi":"10.1038/s44324-026-00123-3","DOIUrl":"10.1038/s44324-026-00123-3","url":null,"abstract":"","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148623617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Timing the strain: skeletal muscle clock as regulator of physical activity.","authors":"Ippei Kawano, Gad Asher","doi":"10.1038/s44324-026-00121-5","DOIUrl":"10.1038/s44324-026-00121-5","url":null,"abstract":"<p><p>Skeletal muscle harbors cell-autonomous circadian clock that is implicated in muscle as well as systemic metabolic and physiological functions. Emerging evidence highlights how the muscle clock integrates time-signals to regulate physical activity. Physical activity imposes recurrent and temporally structured physiological and metabolic perturbations. Here we discuss the literature and propose that the muscle clock is well-positioned to execute anticipatory regulation by engaging metabolic programs in advance of predictable muscle demands.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148623608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation and clinical manifestations of gluconeogenesis dysfunction.","authors":"Natalia Bobok","doi":"10.1038/s44324-026-00120-6","DOIUrl":"10.1038/s44324-026-00120-6","url":null,"abstract":"<p><p>The liver is the principal organ responsible for maintaining systemic glucose homeostasis through the integrated regulation of gluconeogenesis, glycogenolysis, glycogenesis, and glycolysis. As fasting progresses and hepatic glycogen stores decline, gluconeogenesis becomes the dominant source of endogenous glucose production required to preserve euglycemia. This review summarizes the regulation of gluconeogenesis and discusses the clinical manifestations, diagnostic implications, and therapeutic relevance of gluconeogenic dysfunction across diverse disease states.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13388944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148551672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD36: bridging metabolism, inflammation, and reproduction.","authors":"Qian Liu, Dongyong Yang, Songchen Cai, Yujie Zou, Tailang Yin, Lianghui Diao","doi":"10.1038/s44324-026-00109-1","DOIUrl":"10.1038/s44324-026-00109-1","url":null,"abstract":"<p><p>Reproductive success requires coordinated regulation of metabolism and inflammation across the ovary, uterus, and placenta. CD36 is a lipid transporter and innate immune receptor that couples fatty acid handling to lipid-inflammation crosstalk. We synthesize mechanistic evidence on how CD36 regulates oocyte competence, endometrial receptivity, and signaling at the maternal-fetal interface, and how its dysregulation contributes to gestational diabetes, preeclampsia, and pregnancy loss, suggesting CD36 as a therapeutic target.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13376540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148475057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paraoxonases as metabolic and signaling modulators: prospects for therapeutic and preventive implications.","authors":"Sepand Tehrani Fateh, Sahand Tehrani Fateh, Seyed Ali Ziai","doi":"10.1038/s44324-026-00103-7","DOIUrl":"10.1038/s44324-026-00103-7","url":null,"abstract":"<p><p>Paraoxonases (PONs) are a family of three isozymes, PON1, PON2, and PON3, with lactonase and esterase enzymatic activities. These enzymes have been implicated in the pathophysiology of numerous disorders, including cancer, atherosclerosis, liver diseases, neurodegenerative conditions, and toxicities. Specifically, alterations in PONs, such as changes in gene expression, mRNA levels, protein abundance, and enzymatic activity, have been associated with a range of pathological conditions. PONs are primarily linked to these disorders through their antioxidant and detoxifying functions, although additional, yet unidentified, mechanisms may also contribute. A growing body of evidence indicates that modulating PON levels or activity of PONs may confer therapeutic benefit in the prevention, management, and treatment of certain diseases. Promising strategies include enzyme replacement therapy, drug repurposing, and genetic engineering techniques aimed at restoring or enhancing PON function. Moreover, PONs' level and activity can be influenced by life-style factors and the microbiome, offering additional avenues for intervention. In this review, we propose that the modulation of PONs holds therapeutic and preventive potential, and we discuss the current and emerging strategies by which this may be achieved.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13369200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148451285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATP-depleting spreading depolarizations preferentially originate in the somatosensory cortex during in situ energy deprivation.","authors":"Karl Schoknecht, Nicolas G Höck, Felipe Baeza-Lehnert, Jens P Dreier, Johannes Hirrlinger, Jens Eilers","doi":"10.1038/s44324-026-00112-6","DOIUrl":"10.1038/s44324-026-00112-6","url":null,"abstract":"<p><p>Spreading depolarizations (SDs) contribute to acute brain lesion development. While SDs arise in metabolically compromised tissue, regional determinants of SD-susceptibility remain incompletely understood. Here, we show that SDs preferentially originate in the primary somatosensory cortex (S1) during oxygen-glucose deprivation. Notably, before SD initiation, S1 exhibited a more pronounced decline in ATP compared with other brain regions, suggesting S1-specific metabolic vulnerability as a novel working hypothesis underlying SD initiation.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13338157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming in polyol pathway contributes to anti-inflammatory effect of glucosamine salts on synovial fibroblasts.","authors":"Junichi Okada, Rei Nakano, Nanako Kitanaka, Taku Kitanaka, Shinichi Namba, Masumi Nakano, Atsuto Naruke, Junichi Nunomura, Yoko Suwabe, Tadayoshi Konno, Tomoko Tohi, Satoru Kuno, Taro Kimura, Masami Uechi, Tomohiro Nakayama, Jun Yamazaki, Hiroshi Sugiya","doi":"10.1038/s44324-026-00118-0","DOIUrl":"10.1038/s44324-026-00118-0","url":null,"abstract":"<p><p>The upregulation of cyclooxygenase-2 (COX-2) and the subsequent production of prostaglandin E₂ (PGE₂) in synovial tissue are hallmarks of autoimmune arthritis, including rheumatoid arthritis (RA). While glucosamine (GlcN) derivatives modulate RA symptoms, their specific anti-inflammatory mechanisms in synovial fibroblasts (SFBs) are poorly understood. In this study, we evaluated the anti-inflammatory efficacy of various GlcN derivatives: glucosamine hydrochloride (GlcN-HCl), glucosamine sulfate (GlcN-S), glucosaminate (GlcNA), and N-acetylglucosamine (GlcNAc). GlcN-HCl and GlcN-S inhibited IL-1β-induced PGE₂ release and the expression of COX-2 at both protein and mRNA levels, whereas GlcNA and GlcNAc exhibited no such inhibitory activity. Structure-activity relationship analysis using GlcN-HCl epimers revealed that whereas the C-4 epimer, galactosamine hydrochloride (GalN-HCl), retained potent anti-inflammatory effects, the C-2 epimer, mannosamine hydrochloride (ManN-HCl), showed significantly diminished bioactivity, highlighting the critical role of the C-2 stereochemical configuration in modulating inflammatory responses. Mechanistically, we demonstrated that GlcN-HCl-mediated COX-2 suppression occurs via epigenetic silencing rather than mRNA destabilization. GlcN-HCl treatment significantly reduced the enrichment of active chromatin marks, H3K27ac and H3K4me3, at the COX-2 promoter, whereas mRNA stability remained unaffected. Given that metabolic dysregulation is intrinsically linked to inflammatory pathogenesis, we characterized the metabolic profile of GlcN-HCl-treated SFBs. We found that GlcN-HCl triggers metabolic reprogramming of the polyol pathway by modulating the expression of AKR1B1 and sorbitol dehydrogenase (SORD), resulting in elevated intracellular sorbitol levels. Pharmacological inhibition of AKR1B1 effectively abrogated the anti-inflammatory effects of GlcN-HCl, indicating that polyol pathway activation is essential for its efficacy. We confirmed the evolutionary conservation of these findings in human SFBs, demonstrating the translational relevance of the GlcN-HCl-mediated metabolic and epigenetic axis. Our findings demonstrate that GlcN-HCl induces metabolic reprogramming of the polyol pathway in synovial fibroblasts, facilitating the epigenetic silencing of inflammatory mediators. This metabolic-epigenetic axis suggests a mechanistic rationale for pharmacological metabolic intervention in RA, shifting the therapeutic paradigm toward targeted reprogramming of synovial fibroblast metabolism.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13324759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148371639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}