Cell metabolismPub Date : 2025-06-03DOI: 10.1016/j.cmet.2025.05.002
David H. Abbott, Daniel A. Dumesic
{"title":"Monoclonal antibody therapy for PCOS?","authors":"David H. Abbott, Daniel A. Dumesic","doi":"10.1016/j.cmet.2025.05.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.05.002","url":null,"abstract":"There is no cure for polycystic ovary syndrome (PCOS), only treatment for its highly prevalent reproductive, cardiometabolic, and psychological symptoms. Early signs of PCOS appear during infancy. This enabled Cotellessa et al.<span><span><sup>1</sup></span></span> to develop and administer neutralizing antibody therapy during infancy in a female mouse model to eradicate PCOS symptomology.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"7 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144202239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-05-22DOI: 10.1016/j.cmet.2025.05.004
Won-Suk Song, Xiyu Shen, Kang Du, Cuauhtemoc B. Ramirez, Sang Hee Park, Yang Cao, Johnny Le, Hosung Bae, Joohwan Kim, Yujin Chun, Nikki Joyce Khong, Marie Kim, Sunhee Jung, Wonsuk Choi, Miranda L. Lopez, Zaid Said, Zehan Song, Sang-Guk Lee, Dequina Nicholas, Yo Sasaki, Qin Yang
{"title":"Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline","authors":"Won-Suk Song, Xiyu Shen, Kang Du, Cuauhtemoc B. Ramirez, Sang Hee Park, Yang Cao, Johnny Le, Hosung Bae, Joohwan Kim, Yujin Chun, Nikki Joyce Khong, Marie Kim, Sunhee Jung, Wonsuk Choi, Miranda L. Lopez, Zaid Said, Zehan Song, Sang-Guk Lee, Dequina Nicholas, Yo Sasaki, Qin Yang","doi":"10.1016/j.cmet.2025.05.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.05.004","url":null,"abstract":"(Cell Metabolism <em>37</em>, 1–16.e1–e4; July 1, 2025)","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"72 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-05-22DOI: 10.1016/j.cmet.2025.04.018
Júlia Teixidor-Deulofeu, Sebastian Blid Sköldheden, Ferran Font-Gironès, Andrej Feješ, Johan Ruud, Linda Engström Ruud
{"title":"Semaglutide effects on energy balance are mediated by Adcyap1+ neurons in the dorsal vagal complex","authors":"Júlia Teixidor-Deulofeu, Sebastian Blid Sköldheden, Ferran Font-Gironès, Andrej Feješ, Johan Ruud, Linda Engström Ruud","doi":"10.1016/j.cmet.2025.04.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.018","url":null,"abstract":"The use of the GLP-1R agonist semaglutide is revolutionizing the treatment of obesity, yet its mechanistic effects on energy balance remain elusive. Here, we demonstrate that reactivation of semaglutide-responsive dorsal vagal complex neurons mimics the drug’s effects of reducing food intake and body weight and promoting fat utilization and conditioned taste aversion. We observe that many of the semaglutide-activated area postrema (AP) and nucleus of the solitary tract (NTS) neurons express <em>Adcyap1</em> mRNA, and ablation of AP/NTS <em>Adcyap1</em><sup>+</sup> neurons largely reverses semaglutide’s effects on energy balance acutely in lean mice and in subchronically treated obese mice. Semaglutide-activated AP/NTS <em>Adcyap1</em><sup>+</sup> neurons promote the loss of fat rather than lean mass, with only a modest effect on conditioned taste aversion. Furthermore, NTS <em>Adcyap1</em><sup>+</sup> neurons are engaged by GLP-1R-expressing AP neurons and are necessary for semaglutide-induced activation of several downstream satiety-related structures. Selective targeting of semaglutide-responsive <em>Adcyap1</em><sup>+</sup> neurons holds potential for improved future anti-obesity treatments.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"79 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Acetylated cellulose suppresses body mass gain through gut commensals consuming host-accessible carbohydrates","authors":"Tadashi Takeuchi, Eiji Miyauchi, Yumiko Nakanishi, Yusuke Ito, Tamotsu Kato, Katsuki Yaguchi, Masami Kawasumi, Naoko Tachibana, Ayumi Ito, Shu Shimamoto, Akinobu Matsuyama, Nobuo Sasaki, Ikuo Kimura, Hiroshi Ohno","doi":"10.1016/j.cmet.2025.04.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.013","url":null,"abstract":"Effective approaches to preventing and treating obesity are urgently needed. Although current strategies primarily focus on direct modulation of host metabolism, another promising approach may involve limiting nutrient availability through regulation of the gut microbiota, which links diet and host physiology. Here, we report that acetylated cellulose (AceCel), which markedly alters gut bacterial composition and function, reduces body mass gain in both wild-type and obese mice. AceCel limits carbohydrate oxidation and promotes fatty acid oxidation in the host liver in a microbiota-dependent manner. We further show that acetate enhances carbohydrate fermentation by the gut commensal <em>Bacteroides thetaiotaomicron</em>, depleting host-accessible simple sugars in the gut of AceCel-fed mice. These findings highlight the potential of AceCel as a prebiotic that regulates carbohydrate metabolism in both bacteria and host, offering promise as a therapeutic strategy for obesity.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"33 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-05-15DOI: 10.1016/j.cmet.2025.04.016
Yujing Tian, Luwei Kang, Ngoc T. Ha, Juan Deng, Danqian Liu
{"title":"Hydrogen peroxide in midbrain sleep neurons regulates sleep homeostasis","authors":"Yujing Tian, Luwei Kang, Ngoc T. Ha, Juan Deng, Danqian Liu","doi":"10.1016/j.cmet.2025.04.016","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.016","url":null,"abstract":"Sleep could protect animals from oxidative damage, yet the dynamic interplay between the redox state and sleep homeostasis remains unclear. Here, we show that acute sleep deprivation (SD) in mice caused a general increase in brain oxidation, particularly in sleep-promoting regions. <em>In vivo</em> imaging of intracellular hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) real-time dynamics revealed that in nigra sleep neurons, the increase in cytosolic but not mitochondrial H<sub>2</sub>O<sub>2</sub> reflects sleep debt and tracks spontaneous wakefulness by positively correlating with wake duration. By controllably manipulating intraneuronal H<sub>2</sub>O<sub>2</sub>, we discovered that H<sub>2</sub>O<sub>2</sub> elevation is required for compensatory sleep and causally promotes sleep initiation, at least partly dependent on transient receptor potential melastatin 2 (TRPM2) channel. However, excessive H<sub>2</sub>O<sub>2</sub> induced brain inflammation and sleep fragmentation. Together, our study demonstrates intraneuronal H<sub>2</sub>O<sub>2</sub> as a crucial signaling molecule that translates brain redox imbalance into sleep drive and underscores the significance of oxidative eustress in sleep homeostasis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"40 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-05-14DOI: 10.1016/j.cmet.2025.04.015
Jessica W. Davidson, Raghav Jain, Thomas Kizzar, Gisela Geoghegan, Daniel J. Nesbitt, Amy Cavanagh, Akira Abe, Kwamina Nyame, Andrea Hunger, Xiaojuan Chao, Isabella James, Helaina Walesewicz, Dominique A. Baldwin, Gina Wade, Sylwia Michorowska, Rakesh Verma, Kathryn Schueler, Vania Hinkovska-Galcheva, Evgenia Shishkova, Wen-Xing Ding, Judith A. Simcox
{"title":"Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV","authors":"Jessica W. Davidson, Raghav Jain, Thomas Kizzar, Gisela Geoghegan, Daniel J. Nesbitt, Amy Cavanagh, Akira Abe, Kwamina Nyame, Andrea Hunger, Xiaojuan Chao, Isabella James, Helaina Walesewicz, Dominique A. Baldwin, Gina Wade, Sylwia Michorowska, Rakesh Verma, Kathryn Schueler, Vania Hinkovska-Galcheva, Evgenia Shishkova, Wen-Xing Ding, Judith A. Simcox","doi":"10.1016/j.cmet.2025.04.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.015","url":null,"abstract":"Cold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state, shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of <em>Tfeb</em> in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB-binding sites of lysosomal genes and determined that the phospholipase a2 group XV (PLA2G15) regulates BMP lipid catabolism. Decreasing <em>Pla2g15</em> levels in mice increased BMP lipids, ablated the cold-induced rise in BMP lipids, and improved cold tolerance. Mutation of the catalytic site of PLA2G15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through PLA2G15 catabolism.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"39 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-05-13DOI: 10.1016/j.cmet.2025.04.014
Jesse P. Rose, Donald A. Morgan, Andrew I. Sullivan, Xiaorong Fu, Melissa Inigo-Vollmer, Shawn C. Burgess, David K. Meyerholz, Kamal Rahmouni, Matthew J. Potthoff
{"title":"FGF21 reverses MASH through coordinated actions on the CNS and liver","authors":"Jesse P. Rose, Donald A. Morgan, Andrew I. Sullivan, Xiaorong Fu, Melissa Inigo-Vollmer, Shawn C. Burgess, David K. Meyerholz, Kamal Rahmouni, Matthew J. Potthoff","doi":"10.1016/j.cmet.2025.04.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.014","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing public health burden with limited therapeutic options. Recent studies have revealed that fibroblast growth factor 21 (FGF21)-based analogs can significantly improve MASH, but the mechanisms for this effect are not well understood. Here, we demonstrate that the beneficial metabolic effects of FGF21 to reverse MASH are mediated through distinct mechanisms to independently lower hepatic triglyceride and cholesterol levels. Specifically, FGF21 signaling directly to glutamatergic neurons in the central nervous system (CNS) stimulates hepatic triglyceride reduction and reversal of fibrosis, whereas FGF21 signaling directly to hepatocytes is necessary and sufficient to reduce hepatic cholesterol levels in mice. Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver, which suppresses hepatic <em>de novo</em> lipogenesis. These results provide critical insights into a promising pharmacological target to treat MASH.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"41 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The foam cell-derived exosomes exacerbate ischemic white matter injury via transmitting metabolic defects to microglia","authors":"Hang Zhang, Luo-Qi Zhou, Sheng Yang, Ming-Hao Dong, Lian Chen, Yi-Lin Lu, Lu-Yang Zhang, Lan Zhang, Yun-Hui Chu, Lu-Lu Xu, Xiao-Wei Pang, Li-Fang Zhu, Ting Xu, Tu-ying Yong, Wei Wang, Dai-Shi Tian, Chuan Qin","doi":"10.1016/j.cmet.2025.04.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.009","url":null,"abstract":"Atherosclerosis (AS) has been shown to be an independent risk factor for vascular cognitive impairment (VCI), but the mechanisms remain unclear. Here, we found that AS circulating exosomes exacerbated ischemic white matter injury and VCI. Exosomes originating from macrophage-derived foam cells targeted microglia. Mechanistically, foam cell-derived exosomes transmitted redox imbalance, mitochondrial dysfunction, and metabolic defects to microglia via the miR-101-3p-Nrf2-Slc2a1 axis. Anti-miR-101-3p or activation of Nrf2, both genetically and pharmacologically, could antagonize AS exosomes and ameliorate VCI. In conclusion, our findings reveal a distant connection between peripheral macrophages and brain microglia, which provides new insights and potential targets of AS-induced VCI.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"104 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-05-06DOI: 10.1016/j.cmet.2025.04.005
Sungho Jin, Nal Ae Yoon, Mian Wei, Tilla Worgall, Luisa Rubinelli, Tamas L. Horvath, Wei Min, Nadia Diano, Annarita di Lorenzo, Sabrina Diano
{"title":"Endoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior","authors":"Sungho Jin, Nal Ae Yoon, Mian Wei, Tilla Worgall, Luisa Rubinelli, Tamas L. Horvath, Wei Min, Nadia Diano, Annarita di Lorenzo, Sabrina Diano","doi":"10.1016/j.cmet.2025.04.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.005","url":null,"abstract":"Lipid sensing in the hypothalamus contributes to the control of feeding and whole-body metabolism. However, the mechanism responsible for this nutrient-sensing process is ill-defined. Here, we show that Nogo-A, encoded by reticulon 4 (<em>Rtn4</em>) gene and associated with brain development and synaptic plasticity, regulates feeding and energy metabolism by controlling lipid metabolism in Agouti-related protein (AgRP) neurons. Nogo-A expression was upregulated in AgRP neurons of fasted mice and was associated with a significant downregulation of enzymes involved in sphingolipid <em>de novo</em> biosynthesis and the upregulation of key enzymes in intracellular lipid transport and fatty acid oxidation. Deletion of <em>Rtn4</em> in AgRP neurons reduced body weight, ghrelin-induced AgRP activity and food intake, and fasting-induced AgRP activation, together with an increase in ceramide levels. Finally, high-fat-diet-induced obesity induced a significant downregulation of <em>Rtn4</em> and increased ceramide levels in AgRP neurons, suggesting a role for Nogo in AgRP dysregulation in obesity. Taken together, our data reveal that Nogo-A drives AgRP neuronal activity and associated feeding behavior by controlling mitochondrial function and cellular lipid metabolism.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"115 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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