Pub Date : 2025-10-14DOI: 10.1038/s42255-025-01388-6
Mangesh Kurade, Natalia Bobba-Alves, Catherine Kelly, Alexander Behnke, Quinn Conklin, Robert-Paul Juster, Michio Hirano, Caroline Trumpff, Martin Picard
Fibroblast growth factor 21 (FGF21) is a metabolic hormone induced by fasting, metabolic stress and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (P < 0.0001) in healthy controls, but increases FGF21 by 32% (P < 0.0001) in people with MitoD, pointing to a functional FGF21 interaction between the stress response and OxPhos capacity. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report associations between FGF21 and psychosocial factors related to stress and wellbeing. Overall, these results highlight a potential role for FGF21 as a stress hormone involved in meeting the energetic needs of psychosocial stress. FGF21 levels increase in response to acute mental stress in individuals with impaired mitochondrial OxPhos capacity, and correlate with stress-related neuroendocrine hormones and trait-level psychosocial factors.
{"title":"Mitochondrial and psychosocial stress-related regulation of FGF21 in humans","authors":"Mangesh Kurade, Natalia Bobba-Alves, Catherine Kelly, Alexander Behnke, Quinn Conklin, Robert-Paul Juster, Michio Hirano, Caroline Trumpff, Martin Picard","doi":"10.1038/s42255-025-01388-6","DOIUrl":"10.1038/s42255-025-01388-6","url":null,"abstract":"Fibroblast growth factor 21 (FGF21) is a metabolic hormone induced by fasting, metabolic stress and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (P < 0.0001) in healthy controls, but increases FGF21 by 32% (P < 0.0001) in people with MitoD, pointing to a functional FGF21 interaction between the stress response and OxPhos capacity. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report associations between FGF21 and psychosocial factors related to stress and wellbeing. Overall, these results highlight a potential role for FGF21 as a stress hormone involved in meeting the energetic needs of psychosocial stress. FGF21 levels increase in response to acute mental stress in individuals with impaired mitochondrial OxPhos capacity, and correlate with stress-related neuroendocrine hormones and trait-level psychosocial factors.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2212-2220"},"PeriodicalIF":20.8,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288594","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}
Pub Date : 2025-10-13DOI: 10.1038/s42255-025-01387-7
Kasper T. Vinten, Maria M. Trętowicz, Evrim Coskun, Michel van Weeghel, Carles Cantó, Rubén Zapata-Pérez, Georges E. Janssens, Riekelt H. Houtkooper
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.
{"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}
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.
{"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}
Pub Date : 2025-10-07DOI: 10.1038/s42255-025-01381-z
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
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.
食用甜味剂和增甜剂（S&SEs）是减少糖摄入量的一种流行策略，但S&SEs在体重调节和肠道微生物群组成中的作用仍存在争议。在这里，我们发现健康饮食中的s&se支持体重减轻的维持和有益的肠道微生物群在超重或肥胖的成年人中发生变化。在这项多中心、随机、对照试验中，我们纳入了341名超重或肥胖的成年人和38名儿童。成年人遵循2个月的低能量饮食，体重减轻≥5%，随后是10个月的健康随意饮食，糖的能量<10%。一组用S&SE产品代替高糖产品（S&SEs组），而另一组不这样做（糖组）。主要结局包括1年时体重和肠道菌群组成的变化。次要结局包括心脏代谢参数的改变。与糖组相比，S&SEs组在1年后保持了更大的体重减轻（1.6±0.7 kg, P = 0.029），并表现出明显的肠道菌群变化，短链脂肪酸和产甲烷类群增加（q≤0.05）。在心脏代谢标志物或儿童中没有观察到显著差异。总的来说，我们的研究结果表明，在健康饮食中长期食用s&se是一种安全的肥胖管理策略。ClinicalTrial.gov识别码：NCT04226911。
{"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}
Pub Date : 2025-10-07DOI: 10.1038/s42255-025-01382-y
Sarah H. Schmitz, Louis J. Aronne
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.
{"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}
Pub Date : 2025-10-02DOI: 10.1038/s42255-025-01395-7
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
The recent developments in artificial intelligence (AI) have created both intrigue and apprehension in the world of research. In this Viewpoint, we asked 12 experts in the field of metabolism to share their — differing — opinions on the use of AI in pre-clinical and clinical metabolic research.
{"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":"10.1038/s42255-025-01395-7","url":null,"abstract":"The recent developments in artificial intelligence (AI) have created both intrigue and apprehension in the world of research. In this Viewpoint, we asked 12 experts in the field of metabolism to share their — differing — opinions on the use of AI in pre-clinical and clinical metabolic research.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2183-2186"},"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}
Pub Date : 2025-09-30DOI: 10.1038/s42255-025-01367-x
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
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.
{"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}
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).
{"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}
Pub Date : 2025-09-26DOI: 10.1038/s42255-025-01355-1
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
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
{"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}
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