Nature metabolismPub Date : 2025-03-20DOI: 10.1038/s42255-025-01248-3
Sandra Pereira, Margaret K. Hahn
{"title":"GLP-2 attenuates antipsychotics’ adverse metabolic effects","authors":"Sandra Pereira, Margaret K. Hahn","doi":"10.1038/s42255-025-01248-3","DOIUrl":"https://doi.org/10.1038/s42255-025-01248-3","url":null,"abstract":"Antipsychotics are used across severe mental illnesses but cause substantial weight gain and disruption of glucose metabolism. This issue of Nature Metabolism presents findings demonstrating that glucagon-like peptide-2 (GLP-2) minimizes metabolic disruptions caused by the antipsychotic olanzapine.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"92 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661407","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":"GLP-2 prevents antipsychotics-induced metabolic dysfunction in mice","authors":"Yanmin Peng, Chenzhang Feng, Shiyu Peng, Ying Wang, Qian Zhang, Zhuolei Jiao, Huateng Cao, Shajin Huang, Peihuang Tian, Xiujia Sun, Xiaohong Xu, Yu Fu, Ji Hu, Zhe Zhang","doi":"10.1038/s42255-025-01252-7","DOIUrl":"https://doi.org/10.1038/s42255-025-01252-7","url":null,"abstract":"<p>Antipsychotic drugs have severe metabolic side effects. Acute use can induce hypothermia, while chronic use often leads to weight gain and associated disorders. However, no treatment is currently available for drug-induced hypothermia, and weight control measures lack evidence for long-term effectiveness. Here we demonstrate that a glucagon-like peptide 2 analogue, teduglutide, effectively prevents olanzapine-induced hypothermia and weight gain, and restores glucose tolerance and insulin sensitivity in mice. Mechanistically, olanzapine suppresses prodynorphin-expressing neurons in the ventromedial hypothalamus (VMH<sup>Pdyn</sup> neurons) via serotonin receptor 2C, while teduglutide activates the same neuron population. Selective ablation of VMH<sup>Pdyn</sup> neurons mimics olanzapine-induced side effects. More importantly, chemogenetic activation of VMH<sup>Pdyn</sup> neurons abolishes olanzapine-induced hypothermia and excessive weight gain, although the psychotropic effects remain intact. Together, our data show that VMH<sup>Pdyn</sup> neurons are the crucial mediator of antipsychotic-induced metabolic dysfunction and glucagon-like peptide 2 receptor agonism may be an effective target to mitigate both acute and chronic side effects.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661408","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}
Nature metabolismPub Date : 2025-03-18DOI: 10.1038/s42255-025-01242-9
Xin Ma, Cameron J. Shedlock, Terrymar Medina, Roberto A. Ribas, Harrison A. Clarke, Tara R. Hawkinson, Praveen K. Dande, Hari K. R. Golamari, Lei Wu, Borhane EC. Ziani, Sara N. Burke, Matthew E. Merritt, Craig W. Vander Kooi, Matthew S. Gentry, Nirbhay N. Yadav, Li Chen, Ramon C. Sun
{"title":"AI-driven framework to map the brain metabolome in three dimensions","authors":"Xin Ma, Cameron J. Shedlock, Terrymar Medina, Roberto A. Ribas, Harrison A. Clarke, Tara R. Hawkinson, Praveen K. Dande, Hari K. R. Golamari, Lei Wu, Borhane EC. Ziani, Sara N. Burke, Matthew E. Merritt, Craig W. Vander Kooi, Matthew S. Gentry, Nirbhay N. Yadav, Li Chen, Ramon C. Sun","doi":"10.1038/s42255-025-01242-9","DOIUrl":"https://doi.org/10.1038/s42255-025-01242-9","url":null,"abstract":"<p>High-resolution spatial imaging is transforming our understanding of foundational biology. Spatial metabolomics is an emerging field that enables the dissection of the complex metabolic landscape and heterogeneity from a thin tissue section. Currently, spatial metabolism highlights the remarkable complexity in two-dimensional (2D) space and is poised to be extended into the three-dimensional (3D) world of biology. Here we introduce MetaVision3D, a pipeline driven by computer vision, a branch of artificial intelligence focusing on image workflow, for the transformation of serial 2D MALDI mass spectrometry imaging sections into a high-resolution 3D spatial metabolome. Our framework uses advanced algorithms for image registration, normalization and interpolation to enable the integration of serial 2D tissue sections, thereby generating a comprehensive 3D model of unique diverse metabolites across host tissues at submesoscale. As a proof of principle, MetaVision3D was utilized to generate the mouse brain 3D metabolome atlas of normal and diseased animals (available at https://metavision3d.rc.ufl.edu) as an interactive online database and web server to further advance brain metabolism and related research.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641100","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}
Nature metabolismPub Date : 2025-03-17DOI: 10.1038/s42255-025-01237-6
Shaunak Deota, Julie S. Pendergast, Ullas Kolthur-Seetharam, Karyn A. Esser, Frédéric Gachon, Gad Asher, Charna Dibner, Salvador Aznar Benitah, Carolina Escobar, Deborah M. Muoio, Eric Erquan Zhang, Gökhan S. Hotamışlıgil, Joseph Bass, Joseph S. Takahashi, Joshua D. Rabinowitz, Katja A. Lamia, Rafael de Cabo, Shingo Kajimura, Valter D. Longo, Ying Xu, Mitchell A. Lazar, Eric Verdin, Juleen R. Zierath, Johan Auwerx, Daniel J. Drucker, Satchidananda Panda
{"title":"The time is now: accounting for time-of-day effects to improve reproducibility and translation of metabolism research","authors":"Shaunak Deota, Julie S. Pendergast, Ullas Kolthur-Seetharam, Karyn A. Esser, Frédéric Gachon, Gad Asher, Charna Dibner, Salvador Aznar Benitah, Carolina Escobar, Deborah M. Muoio, Eric Erquan Zhang, Gökhan S. Hotamışlıgil, Joseph Bass, Joseph S. Takahashi, Joshua D. Rabinowitz, Katja A. Lamia, Rafael de Cabo, Shingo Kajimura, Valter D. Longo, Ying Xu, Mitchell A. Lazar, Eric Verdin, Juleen R. Zierath, Johan Auwerx, Daniel J. Drucker, Satchidananda Panda","doi":"10.1038/s42255-025-01237-6","DOIUrl":"10.1038/s42255-025-01237-6","url":null,"abstract":"The constant expansion of the field of metabolic research has led to more nuanced and sophisticated understanding of the complex mechanisms that underlie metabolic functions and diseases. Collaborations with scientists of various fields such as neuroscience, immunology and drug discovery have further enhanced the ability to probe the role of metabolism in physiological processes. However, many behaviours, endocrine and biochemical processes, and the expression of genes, proteins and metabolites have daily ~24-h biological rhythms and thus peak only at specific times of the day. This daily variation can lead to incorrect interpretations, lack of reproducibility across laboratories and challenges in translating preclinical studies to humans. In this Review, we discuss the biological, environmental and experimental factors affecting circadian rhythms in rodents, which can in turn alter their metabolic pathways and the outcomes of experiments. We recommend that these variables be duly considered and suggest best practices for designing, analysing and reporting metabolic experiments in a circadian context. This broad group of authors summarizes the impact of circadian factors on metabolic biology and offers recommendations on how to account for and report biological, environmental and experimental factors affecting circadian rhythms in metabolic studies in rodents.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 3","pages":"454-468"},"PeriodicalIF":18.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-025-01237-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635690","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}
Nature metabolismPub Date : 2025-03-14DOI: 10.1038/s42255-025-01228-7
Vera Gorbunova, Andrei Seluanov
{"title":"SIRT5 slows skeletal muscle ageing by alleviating inflammation","authors":"Vera Gorbunova, Andrei Seluanov","doi":"10.1038/s42255-025-01228-7","DOIUrl":"10.1038/s42255-025-01228-7","url":null,"abstract":"Sarcopenia is one of the main contributors to the loss of independence in older adults. A study in primates demonstrates that SIRT5-mediated desuccinylation of TBK1 at Lys137 inhibits the activation of TBK1 and its downstream pro-inflammatory responses, thereby protecting skeletal muscle from ageing.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 3","pages":"447-449"},"PeriodicalIF":18.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618559","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":"SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1","authors":"Qian Zhao, Ying Jing, Xiaoyu Jiang, Xin Zhang, Feifei Liu, Haoyan Huang, Zhihua Zhang, Haijun Wang, Shuhui Sun, Shuai Ma, Weiqi Zhang, Yang Yu, Xiaobing Fu, Guoguang Zhao, Jing Qu, Si Wang, Guang-Hui Liu","doi":"10.1038/s42255-025-01235-8","DOIUrl":"10.1038/s42255-025-01235-8","url":null,"abstract":"Ageing-induced skeletal muscle deterioration contributes to sarcopenia and frailty, adversely impacting the quality of life in the elderly. However, the molecular mechanisms behind primate skeletal muscle ageing remain largely unexplored. Here, we show that SIRT5 expression is reduced in aged primate skeletal muscles from both genders. SIRT5 deficiency in human myotubes hastens cellular senescence and intensifies inflammation. Mechanistically, we demonstrate that TBK1 is a natural substrate for SIRT5. SIRT5 desuccinylates TBK1 at lysine 137, which leads to TBK1 dephosphorylation and the suppression of the downstream inflammatory pathway. Using SIRT5 lentiviral vectors for skeletal muscle gene therapy in male mice enhances physical performance and alleviates age-related muscle dysfunction. This study sheds light on the molecular underpinnings of skeletal muscle ageing and presents the SIRT5–TBK1 pathway as a promising target for combating age-related skeletal muscle degeneration. SIRT5 protects against primate skeletal muscle ageing through TBK1 desuccinylation, which inhibits the downstream inflammatory and senescent phenotypes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 3","pages":"556-573"},"PeriodicalIF":18.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618500","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}
Nature metabolismPub Date : 2025-03-14DOI: 10.1038/s42255-025-01254-5
Mark P. Mattson
{"title":"The cyclic metabolic switching theory of intermittent fasting","authors":"Mark P. Mattson","doi":"10.1038/s42255-025-01254-5","DOIUrl":"https://doi.org/10.1038/s42255-025-01254-5","url":null,"abstract":"<p>Intermittent fasting (IF) and ketogenic diets (KDs) have recently attracted much attention in the scientific literature and in popular culture and follow a longer history of exercise and caloric restriction (CR) research. Whereas IF involves cyclic metabolic switching (CMS) between ketogenic and non-ketogenic states, KDs and CR may not. In this Perspective, I postulate that the beneficial effects of IF result from alternating between activation of adaptive cellular stress response pathways during the fasting period, followed by cell growth and plasticity pathways during the feeding period. Thereby, I establish the cyclic metabolic switching (CMS) theory of IF. The health benefits of IF may go beyond those seen with continuous CR or KDs without CMS owing to the unique interplay between the signalling functions of the ketone β-hydroxybutyrate, mitochondrial adaptations, reciprocal activation of autophagy and mTOR pathways, endocrine and paracrine signalling, gut microbiota, and circadian biology. The CMS theory may have important implications for future basic research, clinical trials, development of pharmacological interventions, and healthy lifestyle practices.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"32 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618712","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":"Human gut microbial aromatic amino acid and related metabolites prevent obesity through intestinal immune control","authors":"Zengliang Jiang, Liuqing He, Diyin Li, Laibao Zhuo, Lingjun Chen, Rui-Qi Shi, Jianhua Luo, Yuhui Feng, Yuhui Liang, Danyang Li, Xiao Congmei, Yuanqing Fu, Yu-ming Chen, Ju-Sheng Zheng, Liang Tao","doi":"10.1038/s42255-025-01246-5","DOIUrl":"https://doi.org/10.1038/s42255-025-01246-5","url":null,"abstract":"<p>Obesity affects millions of people in the world. The gut microbiome influences body fat accumulation, but the mechanisms remain to be investigated. Here, we show an association between microbial aromatic amino acid metabolites in serum and body fat accumulation in a large Chinese longitudinal cohort. We next identify that 4-hydroxyphenylacetic acid (4HPAA) and its analogues effectively protect male mice from high-fat-diet-induced obesity. These metabolites act on intestinal mucosa to regulate the immune response and control lipid uptake, which protects against obesity. We further demonstrate that T cells and B cells are not vital for 4HPAA-mediated obesity prevention, and innate lymphoid cells have antagonistic roles. Together, these findings reveal specific microbial metabolites as pivotal molecules to prohibit obesity through immune control, establishing mechanisms of host modulation by gut microbial metabolites.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"183 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618501","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}
Nature metabolismPub Date : 2025-03-13DOI: 10.1038/s42255-025-01258-1
Rikard Landberg, Therese Karlsson
{"title":"More protein in ultra-processed foods: no shortcut to eating less","authors":"Rikard Landberg, Therese Karlsson","doi":"10.1038/s42255-025-01258-1","DOIUrl":"https://doi.org/10.1038/s42255-025-01258-1","url":null,"abstract":"Short-term intake of protein-enriched ultra-processed foods (UPFs) increased energy expenditure and lowered energy intake compared to UPFs with normal protein content and similar palatability. However, it did not prevent overeating.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"4 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607955","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}