Nature metabolism最新文献

{"title":"NAD+ precursor supplementation in human ageing: clinical evidence and challenges","authors":"Kasper T. Vinten, Maria M. Trętowicz, Evrim Coskun, Michel van Weeghel, Carles Cantó, Rubén Zapata-Pérez, Georges E. Janssens, Riekelt H. Houtkooper","doi":"10.1038/s42255-025-01387-7","DOIUrl":"10.1038/s42255-025-01387-7","url":null,"abstract":"Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism. This Review summarizes existing data, as well as crucial knowledge gaps, emerging from clinical trials involving NAD+ precursor supplementation in humans.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"1974-1990"},"PeriodicalIF":20.8,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infant ketones set the thermogenic tone","authors":"Jing Wang, Da Jia","doi":"10.1038/s42255-025-01357-z","DOIUrl":"10.1038/s42255-025-01357-z","url":null,"abstract":"Infant ketones during breastfeeding reprogram adipose progenitors via epigenetic modifications, driving beige fat development. This confers lifelong obesity resistance and prevents metabolic disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"1963-1964"},"PeriodicalIF":20.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-life ketone body signalling promotes beige fat biogenesis through changes in histone acetylome and β-hydroxybutyrylome","authors":"Chung-Lin Jiang, Pei-Hsiang Lai, Po-Cheng Yang, Chia-Jung Lien, Hsueh-Ping Catherine Chu, Jian-Da Lin, Sung-Jan Lin, I-Shing Yu, Fu-Jung Lin","doi":"10.1038/s42255-025-01378-8","DOIUrl":"10.1038/s42255-025-01378-8","url":null,"abstract":"Infants undergo distinct ketogenesis during the preweaning period, yet its physiological implications remain unclear. Here, we show that preweaning ketosis promotes beige fat biogenesis and improves health outcomes in adulthood. Loss of ketogenesis in neonatal mice by early weaning or ablation of Hmgcs2 hinders beige adipogenesis, subsequently exacerbating metabolic dysregulation in high-fat diet-induced obesity. Enhanced ketogenesis during lactation through exogenous ketone supplements enhances energy expenditure, beige fat formation, and mitochondrial biogenesis and respiration. Using single-cell RNA sequencing, we identified a subset of β-hydroxybutyrate-responsive adipocyte progenitor cells (APCs) expressing Cd81 that showed high beige adipogenic potential. Enhanced ketogenesis promotes the recruitment of beige APCs and their differentiation into beige adipocytes. Mechanistically, ketogenesis-derived βHB induces a switch in the histone acetylome and β-hydroxybutyrylome for transcriptional activation of beige fat biogenesis genes. Notably, enhanced ketogenesis during lactation alleviates adverse metabolic effects predisposed by parental obesity. Our study highlights that targeting preweaning ketosis to drive beige adipogenesis may offer a therapeutic approach to combat obesity and metabolic diseases in adulthood. In the context of parental or diet-induced obesity, preweaning ketosis contributes to improved health outcomes, particularly by regulating the histone acetylome and β-hydroxybutyrylome for transcriptional activation of beige fat biogenesis genes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"2045-2066"},"PeriodicalIF":20.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of sweeteners and sweetness enhancers on weight management and gut microbiota composition in individuals with overweight or obesity: the SWEET study","authors":"Michelle D. Pang, Louise Kjølbæk, Jacco J. A. J. Bastings, Sabina Stoffer Hjorth Andersen, Alexander Umanets, Mônica Maurer Sost, Santiago Navas-Carretero, Kyriakos Reppas, Graham Finlayson, Charo E. Hodgkins, Marta del Álamo, Tony Lam, Hariklia Moshoyiannis, Edith J. M. Feskens, Tanja C. M. Adam, Gijs H. Goossens, Jason C. G. Halford, Joanne A. Harrold, Yannis Manios, J. Alfredo Martinez, Ellen E. Blaak, Anne Raben","doi":"10.1038/s42255-025-01381-z","DOIUrl":"10.1038/s42255-025-01381-z","url":null,"abstract":"Consumption of sweeteners and sweetness enhancers (S&SEs) is a popular strategy to reduce sugar intake, but the role of S&SEs in body weight regulation and gut microbiota composition remains debated. Here, we show that S&SEs in a healthy diet support weight loss maintenance and beneficial gut microbiota shifts in adults with overweight or obesity. In this multi-centre, randomized, controlled trial, we included 341 adults and 38 children with overweight or obesity. Adults followed a 2-month low-energy diet for ≥5% weight loss, followed by a 10-month healthy ad libitum diet with <10% energy from sugars. One group replaced sugar-rich products with S&SE products (S&SEs group), while the other did not (sugar group). Primary outcomes included changes in body weight and gut microbiota composition at 1 year. Secondary outcomes included changes in cardiometabolic parameters. The S&SEs group, compared to the sugar group, maintained greater weight loss at 1 year (1.6 ± 0.7 kg, P = 0.029) and exhibited distinct gut microbiota shifts, with increased short-chain fatty acid and methane-producing taxa (q ≤ 0.05). No significant differences were observed in cardiometabolic markers or in children. Overall, our findings indicate that prolonged consumption of S&SEs in a healthy diet is a safe strategy for obesity management. ClinicalTrial.gov identifier: NCT04226911 . The SWEET project is a multicenter, randomized, controlled trial that shows that long-term consumption of sweeteners and sweetness enhancers improves body weight control and elicits beneficial gut microbiota changes in adults with overweight or obesity.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"2083-2098"},"PeriodicalIF":20.8,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01381-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The SWEET spot for weight maintenance","authors":"Sarah H. Schmitz, Louis J. Aronne","doi":"10.1038/s42255-025-01382-y","DOIUrl":"10.1038/s42255-025-01382-y","url":null,"abstract":"A 12-month multicentre randomized clinical trial finds that replacing added sugar in foods and beverages with sweeteners and sweetness enhancers supports modest weight loss maintenance and alters gut microbiota composition, with no safety concerns identified.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"1968-1969"},"PeriodicalIF":20.8,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence in metabolic research.","authors":"Jens Juul Holst, Camilla Schéele, Philipp E Scherer, Weiping Jia, Eran Segal, Nikolai Slavov, Ruth J F Loos, Golnaz Vahedi, Lei Sun, M Madan Babu, Melissa D McCradden, Peter G Jacobs","doi":"10.1038/s42255-025-01395-7","DOIUrl":"https://doi.org/10.1038/s42255-025-01395-7","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DDHD2 provides a flux of saturated fatty acids for neuronal energy and function","authors":"Saber H. Saber, Nyakuoy Yak, Xuan Ling Hilary Yong, Yih Tyng Bong, Hannah Leeson, Chuan-Yang Dai, Tobias Binder, Siyuan Lu, Reshinthine Purushothaman, An-Sofie Lenaerts, Leonardo Almeida-Souza, Lidiia Koludarova, Safak Er, Irena Hlushchuk, Arnaud Gaudin, Sachin Singh, Tuula A. Nyman, Jeffrey R. Harmer, Steven Zuryn, Ernst Wolvetang, Gert Hoy Talbo, Mikko Airavaara, Brendan J. Battersby, Ashley J. van Waardenberg, Victor Anggono, Giuseppe Balistreri, Merja Joensuu","doi":"10.1038/s42255-025-01367-x","DOIUrl":"10.1038/s42255-025-01367-x","url":null,"abstract":"Although fatty acids support mitochondrial ATP production in most tissues, neurons are believed to rely exclusively on glucose for energy. Here we show that genetic ablation of the triglyceride and phospholipid lipase Ddhd2 impairs mitochondrial respiration and ATP synthesis in cultured neurons, despite increased glycolysis. This defect arises from reduced levels of long-chain saturated free fatty acids, particularly myristic, palmitic and stearic acids, normally released in an activity-dependent manner by Ddhd2. Inhibition of mitochondrial fatty acid import in wild-type neurons similarly reduced mitochondrial respiration and ATP production. Saturated fatty acyl-coenzyme A treatment restored mitochondrial energy production in Ddhd2 knockout neurons. When provided in combination, these activated fatty acyl-CoA supplements also rescued defects in membrane trafficking, synaptic function and protein homeostasis. These findings uncover that neurons perform β-oxidation of endogenous long-chain free fatty acids to meet ATP demands and reveal a potential therapeutic strategy for hereditary spastic paraplegia 54 caused by DDHD2 mutations. Saber et al. show that the lipase DDHD2 provides endogenous saturated fatty acids to support fatty acid oxidation and energy production, proteostasis and membrane trafficking balance.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"2117-2141"},"PeriodicalIF":20.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01367-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shooting for the stars: caspase-8–meteorin in MASH and fibrosis","authors":"Suchira Gallage, Tabea Bieler, Mathias Heikenwalder","doi":"10.1038/s42255-025-01361-3","DOIUrl":"10.1038/s42255-025-01361-3","url":null,"abstract":"In this issue of Nature Metabolism, Wang et al. identified a non-apoptotic caspase-8 function in metabolic dysfunction-associated steatohepatitis (MASH), in which hepatocyte-derived caspase-8 induces meteorin, which in turn activates hepatic stellate cells (HSCs) to drive fibrosis. This function reveals a potential therapeutic target to directly address fibrosis and reduce the progression of metabolic dysfunction-associated steatotic liver disease (MASLD).","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"1965-1967"},"PeriodicalIF":20.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A non-apoptotic caspase-8–meteorin pathway in hepatocytes promotes MASH fibrosis","authors":"Xiaobo Wang, Mary P. Moore, Hongxue Shi, Yang Xiao, Jiayu Zhang, Lanuza A. P. Faccioli, Zhiping Hu, Shareef Khalid, Danish Saleheen, Dwayne G. Stupack, Tatiana Kisseleva, Alejandro Soto Gutierrez, Mitchell A. Lazar, Ira Tabas","doi":"10.1038/s42255-025-01355-1","DOIUrl":"10.1038/s42255-025-01355-1","url":null,"abstract":"Metabolic-dysfunction-associated steatohepatitis (MASH) is the leading cause of chronic liver disease, but an incomplete understanding of MASH-induced liver fibrosis has limited therapeutic options. Here we show that hepatocyte caspase-8 drives MASH fibrosis through an apoptosis-independent mechanism. Hepatic caspase-8 expression correlates with liver fibrosis in both human and experimental MASH, and hepatocyte-specific caspase-8 deletion in male mice with MASH suppressed liver fibrosis and hepatic stellate cell (HSC) activation without affecting hepatocyte apoptosis. Mechanistic studies showed that a caspase-8–YY1 pathway in hepatocytes induces secretory meteorin (Metrn), which activates HSCs via a c-Kit–STAT3 pathway. Meteorin expression was increased in human and male mouse MASH livers and decreased by deletion of hepatocyte caspase-8 in MASH mice and human and mouse primary hepatocytes. Genetic restoration of hepatocyte meteorin in hepatocyte-caspase-8-deleted MASH mice restored HSC activation and liver fibrosis while silencing hepatocyte meteorin lowered liver fibrosis. These findings reveal a therapeutically targetable pathway promoting MASH fibrosis involving a non-apoptotic function of caspase-8 and a newly discovered HSC activator, meteorin. Hepatocyte caspase-8 in MASH promotes the activation of hepatic stellate cells and liver fibrosis through an apoptosis-independent mechanism","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"2067-2082"},"PeriodicalIF":20.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01355-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A salute to innovation: exenatide in diabetes and obesity drug development at Amylin Pharmaceuticals","authors":"James L. Trevaskis, David G. Parkes, Andrew A. Young","doi":"10.1038/s42255-025-01383-x","DOIUrl":"10.1038/s42255-025-01383-x","url":null,"abstract":"The glucagon-like peptide 1 receptor agonist (GLP-1RA) class of medicines has emerged as transformative for the treatment of diabetes, obesity and other diseases. On the twentieth anniversary of the approval of exenatide (Byetta), three former employees of Amylin Pharmaceuticals acknowledge the contributions of some of the individuals and the innovation responsible for delivering the first approved GLP-1RA — the forerunner to the modern blockbuster drugs.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"1960-1962"},"PeriodicalIF":20.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140440","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}