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Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes 单核转录组学识别出不同类别的 UCP1 和无效周期脂肪细胞
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-07-30 DOI: 10.1016/j.cmet.2024.07.005
{"title":"Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes","authors":"","doi":"10.1016/j.cmet.2024.07.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.005","url":null,"abstract":"<p>Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of <em>Ucp1</em>. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"143 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794969","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}
引用次数: 0
Development of a functional beige fat cell line uncovers independent subclasses of cells expressing UCP1 and the futile creatine cycle 功能性米色脂肪细胞系的开发揭示了表达 UCP1 和无效肌酸循环的独立细胞亚类
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-07-30 DOI: 10.1016/j.cmet.2024.07.002
{"title":"Development of a functional beige fat cell line uncovers independent subclasses of cells expressing UCP1 and the futile creatine cycle","authors":"","doi":"10.1016/j.cmet.2024.07.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.002","url":null,"abstract":"<p>Although uncoupling protein 1 (UCP1) is established as a major contributor to adipose thermogenesis, recent data have illustrated an important role for alternative pathways, particularly the futile creatine cycle (FCC). How these pathways co-exist in cells and tissues has not been explored. Beige cell adipogenesis occurs <em>in vivo</em> but has been difficult to model <em>in vitro</em>; here, we describe the development of a murine beige cell line that executes a robust respiratory response, including uncoupled respiration and the FCC. The key FCC enzyme, tissue-nonspecific alkaline phosphatase (TNAP), is localized almost exclusively to mitochondria in these cells. Surprisingly, single-cell cloning from this cell line shows that cells with the highest levels of UCP1 express little TNAP, and cells with the highest expression of TNAP express little UCP1. Immunofluorescence analysis of subcutaneous fat from cold-exposed mice confirms that the highest levels of these critical thermogenic components are expressed in distinct fat cell populations.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"61 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794972","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}
引用次数: 0
A microbial metabolite inhibits the HIF-2α-ceramide pathway to mediate the beneficial effects of time-restricted feeding on MASH 一种微生物代谢物抑制 HIF-2α 神经酰胺通路，从而介导限时进食对 MASH 的有益影响
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-07-29 DOI: 10.1016/j.cmet.2024.07.004
{"title":"A microbial metabolite inhibits the HIF-2α-ceramide pathway to mediate the beneficial effects of time-restricted feeding on MASH","authors":"","doi":"10.1016/j.cmet.2024.07.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.004","url":null,"abstract":"<p>Time-restricted feeding (TRF) is a potent dietary intervention for improving metabolic diseases, including metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH). However, the mechanism of this efficacy has remained elusive. Here, we show that TRF improves MASLD, which is associated with a significant enrichment of <em>Ruminococcus torques</em> (<em>R. torques</em>). Mechanistically, <em>R. torques</em> suppresses the intestinal HIF-2α-ceramide pathway via the production of 2-hydroxy-4-methylpentanoic acid (HMP). We identify <em>rtMor</em> as a 4-methyl-2-oxopentanoate reductase that synthesizes HMP in <em>R. torques</em>. Finally, we show that either the colonization of <em>R. torques</em> or oral HMP supplementation can ameliorate inflammation and fibrosis in a MASH mouse model. These findings identify <em>R. torques</em> and HMP as potential TRF mimetics for the treatment of metabolic disorders.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"356 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794970","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}
引用次数: 0
International consensus on fasting terminology 关于禁食术语的国际共识
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-07-25 DOI: 10.1016/j.cmet.2024.06.013
{"title":"International consensus on fasting terminology","authors":"","doi":"10.1016/j.cmet.2024.06.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.06.013","url":null,"abstract":"<p>Although fasting is increasingly applied for disease prevention and treatment, consensus on terminology is lacking. Using Delphi methodology, an international, multidisciplinary panel of researchers and clinicians standardized definitions of various fasting approaches in humans. Five online surveys and a live online conference were conducted with 38 experts, 25 of whom completed all 5 surveys. Consensus was achieved for the following terms: “fasting” (voluntary abstinence from some or all foods or foods and beverages), “modified fasting” (restriction of energy intake to max. 25% of energy needs), “fluid-only fasting,” “alternate-day fasting,” “short-term fasting” (lasting 2–3 days), “prolonged fasting” (≥4 consecutive days), and “religious fasting.” “Intermittent fasting” (repetitive fasting periods lasting ≤48 h), “time-restricted eating,” and “fasting-mimicking diet” were discussed most. This study provides expert recommendations on fasting terminology for future research and clinical applications, facilitating communication and cross-referencing in the field.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"47 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764460","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}
引用次数: 0
Cyclic fasting-mimicking diet in cancer treatment: Preclinical and clinical evidence 癌症治疗中的循环性禁食模拟饮食：临床前和临床证据
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-07-25 DOI: 10.1016/j.cmet.2024.06.014
{"title":"Cyclic fasting-mimicking diet in cancer treatment: Preclinical and clinical evidence","authors":"","doi":"10.1016/j.cmet.2024.06.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.06.014","url":null,"abstract":"<p>In preclinical tumor models, cyclic fasting and fasting-mimicking diets (FMDs) produce antitumor effects that become synergistic when combined with a wide range of standard anticancer treatments while protecting normal tissues from treatment-induced adverse events.</p><p>More recently, results of phase 1/2 clinical trials showed that cyclic FMD is safe, feasible, and associated with positive metabolic and immunomodulatory effects in patients with different tumor types, thus paving the way for larger clinical trials to investigate FMD anticancer activity in different clinical contexts.</p><p>Here, we review the tumor-cell-autonomous and immune-system-mediated mechanisms of fasting/FMD antitumor effects, and we critically discuss new metabolic interventions that could synergize with nutrient starvation to boost its anticancer activity and prevent or reverse tumor resistance while minimizing toxicity to patients. Finally, we highlight potential future applications of FMD approaches in combination with standard anticancer strategies as well as strategies to implement the design and conduction of clinical trials.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"65 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754327","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}
引用次数: 0
Brain responses to intermittent fasting and the healthy living diet in older adults 老年人大脑对间歇性禁食和健康生活饮食的反应
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-07-16 DOI: 10.1016/j.cmet.2024.07.012
{"title":"Brain responses to intermittent fasting and the healthy living diet in older adults","authors":"","doi":"10.1016/j.cmet.2024.07.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.07.012","url":null,"abstract":"No Abstract","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"72 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625173","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}
引用次数: 0
A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation Th17 细胞内在谷胱甘肽/微粒体-IL-22 轴可防止肠道炎症
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-07-09 DOI: 10.1016/j.cmet.2024.06.010
Lynn Bonetti, Veronika Horkova, Melanie Grusdat, Joseph Longworth, Luana Guerra, Henry Kurniawan, Davide G. Franchina, Leticia Soriano-Baguet, Carole Binsfeld, Charlène Verschueren, Sabine Spath, Anouk Ewen, Eric Koncina, Jean-Jacques Gérardy, Takumi Kobayashi, Catherine Dostert, Sophie Farinelle, Janika Härm, Yu-Tong Fan, Ying Chen, Dirk Brenner
{"title":"A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation","authors":"Lynn Bonetti, Veronika Horkova, Melanie Grusdat, Joseph Longworth, Luana Guerra, Henry Kurniawan, Davide G. Franchina, Leticia Soriano-Baguet, Carole Binsfeld, Charlène Verschueren, Sabine Spath, Anouk Ewen, Eric Koncina, Jean-Jacques Gérardy, Takumi Kobayashi, Catherine Dostert, Sophie Farinelle, Janika Härm, Yu-Tong Fan, Ying Chen, Dirk Brenner","doi":"10.1016/j.cmet.2024.06.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.06.010","url":null,"abstract":"<p>The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (<em>Gclc</em>), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, <em>Gclc</em> deficiency did not alter cytokine secretion; however, <em>C. rodentium</em> infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"35 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561667","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}
引用次数: 0
Biological and genetic determinants of glycolysis: Phosphofructokinase isoforms boost energy status of stored red blood cells and transfusion outcomes 糖酵解的生物和遗传决定因素：磷酸果糖激酶同工酶促进储存红细胞的能量状态和输血结果
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-07-03 DOI: 10.1016/j.cmet.2024.06.007
Travis Nemkov, Daniel Stephenson, Eric J. Earley, Gregory R. Keele, Ariel Hay, Alicia Key, Zachary B. Haiman, Christopher Erickson, Monika Dzieciatkowska, Julie A. Reisz, Amy Moore, Mars Stone, Xutao Deng, Steven Kleinman, Steven L. Spitalnik, Eldad A. Hod, Krystalyn E. Hudson, Kirk C. Hansen, Bernhard O. Palsson, Gary A. Churchill, Angelo D’Alessandro
{"title":"Biological and genetic determinants of glycolysis: Phosphofructokinase isoforms boost energy status of stored red blood cells and transfusion outcomes","authors":"Travis Nemkov, Daniel Stephenson, Eric J. Earley, Gregory R. Keele, Ariel Hay, Alicia Key, Zachary B. Haiman, Christopher Erickson, Monika Dzieciatkowska, Julie A. Reisz, Amy Moore, Mars Stone, Xutao Deng, Steven Kleinman, Steven L. Spitalnik, Eldad A. Hod, Krystalyn E. Hudson, Kirk C. Hansen, Bernhard O. Palsson, Gary A. Churchill, Angelo D’Alessandro","doi":"10.1016/j.cmet.2024.06.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.06.007","url":null,"abstract":"<p>Mature red blood cells (RBCs) lack mitochondria and thus exclusively rely on glycolysis to generate adenosine triphosphate (ATP) during aging <em>in vivo</em> or storage in blood banks. Here, we leveraged 13,029 volunteers from the Recipient Epidemiology and Donor Evaluation Study to identify associations between end-of-storage levels of glycolytic metabolites and donor age, sex, and ancestry-specific genetic polymorphisms in regions encoding phosphofructokinase 1, platelet (detected in mature RBCs); hexokinase 1 (HK1); and ADP-ribosyl cyclase 1 and 2 (CD38/BST1). Gene-metabolite associations were validated in fresh and stored RBCs from 525 Diversity Outbred mice and via multi-omics characterization of 1,929 samples from 643 human RBC units during storage. ATP and hypoxanthine (HYPX) levels—and the genetic traits linked to them—were associated with hemolysis <em>in vitro</em> and <em>in vivo</em>, both in healthy autologous transfusion recipients and in 5,816 critically ill patients receiving heterologous transfusions, suggesting their potential as markers to improve transfusion outcomes.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"93 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496022","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}
引用次数: 0
Association of genetic risk, lifestyle, and their interaction with obesity and obesity-related morbidities 遗传风险、生活方式及其与肥胖和肥胖相关疾病的相互作用的关系
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-07-02 DOI: 10.1016/j.cmet.2024.06.004
Min Seo Kim, Injeong Shim, Akl C. Fahed, Ron Do, Woong-Yang Park, Pradeep Natarajan, Amit V. Khera, Hong-Hee Won
{"title":"Association of genetic risk, lifestyle, and their interaction with obesity and obesity-related morbidities","authors":"Min Seo Kim, Injeong Shim, Akl C. Fahed, Ron Do, Woong-Yang Park, Pradeep Natarajan, Amit V. Khera, Hong-Hee Won","doi":"10.1016/j.cmet.2024.06.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.06.004","url":null,"abstract":"<p>The extent to which modifiable lifestyle factors offset the determined genetic risk of obesity and obesity-related morbidities remains unknown. We explored how the interaction between genetic and lifestyle factors influences the risk of obesity and obesity-related morbidities. The polygenic score for body mass index was calculated to quantify inherited susceptibility to obesity in 338,645 UK Biobank European participants, and a composite lifestyle score was derived from five obesogenic factors (physical activity, diet, sedentary behavior, alcohol consumption, and sleep duration). We observed significant interaction between high genetic risk and poor lifestyles (<em>p</em><sub>interaction</sub> &lt; 0.001). Absolute differences in obesity risk between those who adhere to healthy lifestyles and those who do not had gradually expanded with an increase in polygenic score. Despite a high genetic risk for obesity, individuals can prevent obesity-related morbidities by adhering to a healthy lifestyle and maintaining a normal body weight. Healthy lifestyles should be promoted irrespective of genetic background.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"44 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489802","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}
引用次数: 0
From whence it came: Mitochondrial mRNA leaves, a protein returns 从哪里来线粒体 mRNA 离去，蛋白质归来
IF 29 1区 生物学
Cell metabolism Pub Date : 2024-07-02 DOI: 10.1016/j.cmet.2024.06.002
Kevin A. Janssen, Angela Song
{"title":"From whence it came: Mitochondrial mRNA leaves, a protein returns","authors":"Kevin A. Janssen, Angela Song","doi":"10.1016/j.cmet.2024.06.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.06.002","url":null,"abstract":"<p>Small peptides have previously been reported to be encoded in mitochondrial rRNA and translated by cytosolic ribosomes. In this issue of <em>Cell Metabolism</em>, Hu et al. use mass spectrometry to identify a cytosolically translated protein, encoded instead in mitochondrial mRNA, that is surprisingly targeted back into the mitochondrial matrix.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"2015 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489682","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}
引用次数: 0
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