Pub Date : 2026-01-12DOI: 10.1016/j.cmet.2025.12.014
Azusa Terasaki, Keshav Bhatnagar, Alexis T. Weiner, Yuhao Tan, Viktoria Szeifert, Han-Li Huang, Lukas Wiggers, Viviana Rodrigues, Cara C. Rada, Vishnu Shankar, Suguru Saito, Peter Ofori Ankomah, Theodore Roth, Bill Chiu, Robert West, Lingyin Li, Nathan Reticker-Flynn, Jeffrey D. Axelrod, Jonathan R. Brestoff, Bo Li, Edgar Engleman, Derick Okwan-Duodu
Although the immune system is a significant barrier to tumor growth and spread, established tumors evade immune attack and frequently colonize immune populated areas such as the lymph node. The mechanisms by which cancer cells subvert the tumor-immune microenvironment to favor spread to the lymph node remain incompletely understood. Here, we show that, as a common attribute, tumor cells hijack mitochondria from a wide array of immune cells. Mitochondria loss by immune cells decreases antigen-presentation and co-stimulatory machinery, as well as reducing the activation and cytotoxic capacity of natural killer (NK) and CD8 T cells. In cancer cells, the exogenous mitochondria fuse with endogenous mitochondria networks, leak mtDNA into the cytosol, and stimulate cGAS/STING, activating type I interferon-mediated immune evasion programs. Blocking mitochondrial transfer machinery-including cGAS, STING, or type I interferon-reduced cancer metastasis to the lymph node. These findings suggest that cancer cells leverage mitochondria hijacking to weaken anti-tumor immunosurveillance and use the acquired mitochondria to fuel the immunological requirements of lymph node colonization.
{"title":"Mitochondrial transfer from immune to tumor cells enables lymph node metastasis","authors":"Azusa Terasaki, Keshav Bhatnagar, Alexis T. Weiner, Yuhao Tan, Viktoria Szeifert, Han-Li Huang, Lukas Wiggers, Viviana Rodrigues, Cara C. Rada, Vishnu Shankar, Suguru Saito, Peter Ofori Ankomah, Theodore Roth, Bill Chiu, Robert West, Lingyin Li, Nathan Reticker-Flynn, Jeffrey D. Axelrod, Jonathan R. Brestoff, Bo Li, Edgar Engleman, Derick Okwan-Duodu","doi":"10.1016/j.cmet.2025.12.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.12.014","url":null,"abstract":"Although the immune system is a significant barrier to tumor growth and spread, established tumors evade immune attack and frequently colonize immune populated areas such as the lymph node. The mechanisms by which cancer cells subvert the tumor-immune microenvironment to favor spread to the lymph node remain incompletely understood. Here, we show that, as a common attribute, tumor cells hijack mitochondria from a wide array of immune cells. Mitochondria loss by immune cells decreases antigen-presentation and co-stimulatory machinery, as well as reducing the activation and cytotoxic capacity of natural killer (NK) and CD8 T cells. In cancer cells, the exogenous mitochondria fuse with endogenous mitochondria networks, leak mtDNA into the cytosol, and stimulate cGAS/STING, activating type I interferon-mediated immune evasion programs. Blocking mitochondrial transfer machinery-including cGAS, STING, or type I interferon-reduced cancer metastasis to the lymph node. These findings suggest that cancer cells leverage mitochondria hijacking to weaken anti-tumor immunosurveillance and use the acquired mitochondria to fuel the immunological requirements of lymph node colonization.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"40 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961694","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}
Pub Date : 2026-01-09DOI: 10.1016/j.cmet.2025.12.015
Yunhui Li, Ting Lei, Wen Nie, Mingrui Ma, Wei Zhao, Ye Zhou, Yanfang Liu, Minjun Wang, Kaiwei Jia, Shanrong Liu, Yuanyuan Wang, Yiwen Fan, Long Chen, Xing He, Jihang Yuan, Xuetao Cao, Jin Hou
Intracellular membraneless organelles, including granules, bodies, speckles, etc., play critical roles in physiological and pathological processes. The discovery of new membraneless organelles has generated significant attention. DEAD-box helicase (DDX) family members possess the potential to undergo liquid-liquid phase separation (LLPS), the foundation for the assembly of membraneless organelles. Here, to identify new granules assembled in steatotic hepatocytes, we screened DDX family members and found that lipids, especially arachidonic acid (AA) metabolites, induced LLPS of DDX49 in hepatocytes, forming an assembled granule named as lipid-induced granule (LIG). The assembled LIGs by DDX49 feedback restrained metabolic dysfunction-associated steatotic liver disease (MASLD)-associated fibrosis. Mechanistically, C5-methylcytosine (m5C)-modified mRNA of pro-fibrotic hepatokine tissue inhibitor of metalloproteinase 2 (Timp2) and its reader Y-box binding protein 1 (YBX1) were recruited into LIGs, thereby inhibiting Timp2 mRNA translation and consequently feedback suppressing liver fibrosis. Moreover, LIGs were identified in human MASLD livers and exhibited reverse correlation with fibrosis progression. Therefore, we identified a new granule in steatotic hepatocytes and elucidated its role in restraining liver fibrosis.
{"title":"Lipid-induced granules in hepatocytes alleviate liver fibrosis","authors":"Yunhui Li, Ting Lei, Wen Nie, Mingrui Ma, Wei Zhao, Ye Zhou, Yanfang Liu, Minjun Wang, Kaiwei Jia, Shanrong Liu, Yuanyuan Wang, Yiwen Fan, Long Chen, Xing He, Jihang Yuan, Xuetao Cao, Jin Hou","doi":"10.1016/j.cmet.2025.12.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.12.015","url":null,"abstract":"Intracellular membraneless organelles, including granules, bodies, speckles, etc., play critical roles in physiological and pathological processes. The discovery of new membraneless organelles has generated significant attention. DEAD-box helicase (DDX) family members possess the potential to undergo liquid-liquid phase separation (LLPS), the foundation for the assembly of membraneless organelles. Here, to identify new granules assembled in steatotic hepatocytes, we screened DDX family members and found that lipids, especially arachidonic acid (AA) metabolites, induced LLPS of DDX49 in hepatocytes, forming an assembled granule named as lipid-induced granule (LIG). The assembled LIGs by DDX49 feedback restrained metabolic dysfunction-associated steatotic liver disease (MASLD)-associated fibrosis. Mechanistically, C5-methylcytosine (m<sup>5</sup>C)-modified mRNA of pro-fibrotic hepatokine tissue inhibitor of metalloproteinase 2 (<em>Timp2</em>) and its reader Y-box binding protein 1 (YBX1) were recruited into LIGs, thereby inhibiting <em>Timp2</em> mRNA translation and consequently feedback suppressing liver fibrosis. Moreover, LIGs were identified in human MASLD livers and exhibited reverse correlation with fibrosis progression. Therefore, we identified a new granule in steatotic hepatocytes and elucidated its role in restraining liver fibrosis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"43 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937995","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}
Pub Date : 2026-01-09DOI: 10.1016/j.cmet.2025.12.009
Anand Kumar Sharma, Radhika Khandelwal, Jelena Zurkovic, Fen Long, Tongtong Wang, Revati S. Dewal, Chunyan Wu, Adhideb Ghosh, Klug Manuel, Alaa Othman, Chandramohan Chitraju, Robert V. Farese, Tobias C. Walther, Miroslav Balaz, Christoph Thiele, Christian Wolfrum
Thermoregulation is an essential yet incompletely understood homeostatic process in mammals. UCP1-mediated thermogenesis, while efficient, is dispensable, suggesting the existence of alternative mechanisms. Using a pharmacogenetic approach, we show that the adipose tissue futile lipid cycling (FLC) contributes to UCP1-independent thermogenesis, with DGATs being involved in the regulation of FLC. The loss of DGAT-driven FLC-mediated thermogenesis is compensated for by the hierarchical recruitment of alternative mechanisms such as shivering and enhanced lipid catabolism mediated by AMPK activation. Consistently, pharmacological inhibition of muscle shivering or AMPK in FLC-deficient mice leads to an acute reduction in energy expenditure and hypothermia. These findings demonstrate a substantial thermogenic potential of FLC and suggest previously unappreciated flexibility and adaptability in regulating the core body temperature through adaptive changes in adipocyte metabolism.
{"title":"DGAT-driven futile lipid cycling has a pronounced, yet concealed, thermogenic function","authors":"Anand Kumar Sharma, Radhika Khandelwal, Jelena Zurkovic, Fen Long, Tongtong Wang, Revati S. Dewal, Chunyan Wu, Adhideb Ghosh, Klug Manuel, Alaa Othman, Chandramohan Chitraju, Robert V. Farese, Tobias C. Walther, Miroslav Balaz, Christoph Thiele, Christian Wolfrum","doi":"10.1016/j.cmet.2025.12.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.12.009","url":null,"abstract":"Thermoregulation is an essential yet incompletely understood homeostatic process in mammals. UCP1-mediated thermogenesis, while efficient, is dispensable, suggesting the existence of alternative mechanisms. Using a pharmacogenetic approach, we show that the adipose tissue futile lipid cycling (FLC) contributes to UCP1-independent thermogenesis, with DGATs being involved in the regulation of FLC. The loss of DGAT-driven FLC-mediated thermogenesis is compensated for by the hierarchical recruitment of alternative mechanisms such as shivering and enhanced lipid catabolism mediated by AMPK activation. Consistently, pharmacological inhibition of muscle shivering or AMPK in FLC-deficient mice leads to an acute reduction in energy expenditure and hypothermia. These findings demonstrate a substantial thermogenic potential of FLC and suggest previously unappreciated flexibility and adaptability in regulating the core body temperature through adaptive changes in adipocyte metabolism.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"369 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920207","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}
Pub Date : 2026-01-06DOI: 10.1016/j.cmet.2025.11.015
Fiorella Di Pastena, Jaya Gautam, James S.V. Lally, Russta Fayyazi, Estelle Grasset, Dipankar Bhattacharya, Gio Fidelito, Elham Ahmadi, Logan K. Townsend, Battsetseg Batchuluun, Daniela Carmen Oniciu, Spencer Heaton, Roger S. Newton, Theodoros Tsakiridis, Evangelia E. Tsakiridis, Suhrid Banskota, Parneet Deo, François Briand, Kat Hall, Eunice Lee, Gregory R. Steinberg
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, and fibrosis driven by hepatic stellate cell (HSC) activation. Acetyl-CoA is central to de novo lipogenesis (DNL) and cholesterol synthesis and is generated from citrate via ATP citrate lyase (ACLY) or from acetate via acetyl-CoA synthetase (ACSS2). Here, we demonstrate that a dual inhibitor of ACLY and ACSS2, EVT0185, reduces serum and liver triglycerides, insulin resistance, and fibrosis. EVT0185 directly suppresses HSC activation in vivo and in vitro, with spatial transcriptomics and single-cell RNA sequencing revealing inhibition of acetate metabolism via ACSS2 and cholesterol synthesis as key drivers of the phenotype. EVT0185 also inhibits de novo lipogenesis in human liver slices and blocks TGFβ1-induced activation of primary human HSCs. These findings suggest that targeting cholesterol and acetate metabolism through dual ACLY and ACSS2 inhibition represents a promising therapeutic approach for MASH and liver fibrosis.
{"title":"Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH","authors":"Fiorella Di Pastena, Jaya Gautam, James S.V. Lally, Russta Fayyazi, Estelle Grasset, Dipankar Bhattacharya, Gio Fidelito, Elham Ahmadi, Logan K. Townsend, Battsetseg Batchuluun, Daniela Carmen Oniciu, Spencer Heaton, Roger S. Newton, Theodoros Tsakiridis, Evangelia E. Tsakiridis, Suhrid Banskota, Parneet Deo, François Briand, Kat Hall, Eunice Lee, Gregory R. Steinberg","doi":"10.1016/j.cmet.2025.11.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.11.015","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, and fibrosis driven by hepatic stellate cell (HSC) activation. Acetyl-CoA is central to <em>de novo</em> lipogenesis (DNL) and cholesterol synthesis and is generated from citrate via ATP citrate lyase (ACLY) or from acetate via acetyl-CoA synthetase (ACSS2). Here, we demonstrate that a dual inhibitor of ACLY and ACSS2, EVT0185, reduces serum and liver triglycerides, insulin resistance, and fibrosis. EVT0185 directly suppresses HSC activation <em>in vivo</em> and <em>in vitro</em>, with spatial transcriptomics and single-cell RNA sequencing revealing inhibition of acetate metabolism via ACSS2 and cholesterol synthesis as key drivers of the phenotype. EVT0185 also inhibits <em>de novo</em> lipogenesis in human liver slices and blocks TGFβ1-induced activation of primary human HSCs. These findings suggest that targeting cholesterol and acetate metabolism through dual ACLY and ACSS2 inhibition represents a promising therapeutic approach for MASH and liver fibrosis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"31 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907941","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}
Pub Date : 2026-01-06DOI: 10.1016/j.cmet.2025.11.017
Ioannis G. Lempesis, Frank A.J.L. Scheer
Humankind currently lives largely under artificial light, potentially negatively impacting circadian-metabolic alignment and predisposing it to diseases. Harmsen et al.1 show that natural daylight exposure during office hours improves several metabolic parameters including glucose regulation, enhancing fat oxidation, and advancing muscle-clock circadian phase in individuals with type 2 diabetes.
{"title":"Illuminating the influence of natural daylight on human metabolism","authors":"Ioannis G. Lempesis, Frank A.J.L. Scheer","doi":"10.1016/j.cmet.2025.11.017","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.11.017","url":null,"abstract":"Humankind currently lives largely under artificial light, potentially negatively impacting circadian-metabolic alignment and predisposing it to diseases. Harmsen et al.<span><span><sup>1</sup></span></span> show that natural daylight exposure during office hours improves several metabolic parameters including glucose regulation, enhancing fat oxidation, and advancing muscle-clock circadian phase in individuals with type 2 diabetes.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"57 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907940","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}
Pub Date : 2026-01-06DOI: 10.1016/j.cmet.2025.12.001
David S. Ludwig
Section snippets
Main text
The complexity of nutrition and human behavior poses a major challenge to the study of diet-disease relationships, prompting some researchers to adopt a feeding study design. Conceptually, feeding studies provide an opportunity to isolate the effects of a single dietary factor of interest, controlling for confounding influences. Toward this end, Preston et al.1 conducted a macronutrient-controlled 2-by-2 cross-over feeding trial comparing an ultra-processed food (UPF) diet with an “unprocessed”
Acknowledgments
This work was done without financial sponsorship.
Declaration of interests
D.S.L. received royalties for books on obesity and nutrition that recommend a reduced glycemic load diet.
{"title":"Confusion about energy and energy density in a 3-week trial of ultra-processed food","authors":"David S. Ludwig","doi":"10.1016/j.cmet.2025.12.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.12.001","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>The complexity of nutrition and human behavior poses a major challenge to the study of diet-disease relationships, prompting some researchers to adopt a feeding study design. Conceptually, feeding studies provide an opportunity to isolate the effects of a single dietary factor of interest, controlling for confounding influences. Toward this end, Preston et al.<sup>1</sup> conducted a macronutrient-controlled 2-by-2 cross-over feeding trial comparing an ultra-processed food (UPF) diet with an “unprocessed”</section></section><section><section><h2>Acknowledgments</h2>This work was done without financial sponsorship.</section></section><section><section><h2>Declaration of interests</h2>D.S.L. received royalties for books on obesity and nutrition that recommend a reduced glycemic load diet.</section></section>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"29 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902688","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}
Pub Date : 2025-12-19DOI: 10.1016/j.cmet.2025.11.012
María Ángeles Cáliz-Molina, Raúl López-Fernández-Sobrino, Inmaculada Pino-Pérez, Concepción Panadero-Morón, María del Carmen Vilches-Pérez, María Camacho-Cabrera, Almudena García-Ruiz, Leopoldo Pérez-Rosendo, Isabel Espadas, Alejandro Sola-García, Mario Soriano-Navarro, Franz Martin, Mónica Venegas-Calerón, Joaquín Jesús Salas, Enrique Martínez-Force, Luis C. Romero, Ángeles Aroca, Román González-Prieto, Máximo Bernabeu-Wittel, Vivian Capilla-González, Christopher Hine, Alejandro Martín-Montalvo
{"title":"Enhanced non-enzymatic H2S generation extends lifespan and healthspan in male mice","authors":"María Ángeles Cáliz-Molina, Raúl López-Fernández-Sobrino, Inmaculada Pino-Pérez, Concepción Panadero-Morón, María del Carmen Vilches-Pérez, María Camacho-Cabrera, Almudena García-Ruiz, Leopoldo Pérez-Rosendo, Isabel Espadas, Alejandro Sola-García, Mario Soriano-Navarro, Franz Martin, Mónica Venegas-Calerón, Joaquín Jesús Salas, Enrique Martínez-Force, Luis C. Romero, Ángeles Aroca, Román González-Prieto, Máximo Bernabeu-Wittel, Vivian Capilla-González, Christopher Hine, Alejandro Martín-Montalvo","doi":"10.1016/j.cmet.2025.11.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.11.012","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"37 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784404","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}
Pub Date : 2025-12-18DOI: 10.1016/j.cmet.2025.11.006
Jan-Frieder Harmsen, Ivo Habets, Andrew D. Biancolin, Agata Lesniewska, Nicholas E. Phillips, Loic Metz, Juan Sanchez-Avila, Marit Kotte, Merel Timmermans, Dzhansel Hashim, Soraya S. de Kam, Gert Schaart, Johanna A. Jörgensen, Anne Gemmink, Esther Moonen-Kornips, Daniel Doligkeit, Tineke van de Weijer, Mijke Buitinga, Florian Haans, Rebecca De Lorenzo, Joris Hoeks
Because 80%–90% of our time is spent indoors and daylight is the main synchronizer of the central biological clock, the chronic lack of daylight is increasingly considered as a risk factor for metabolic diseases, such as type 2 diabetes. In a randomized crossover design (NCT05263232), 13 individuals with type 2 diabetes were exposed to natural daylight facilitated through windows vs. constant artificial lighting during office hours for 4.5 consecutive days. Continuous glucose monitoring revealed that participants spent more time in the normal glucose range, and whole-body substrate metabolism shifted toward a greater reliance on fat oxidation during daylight. Primary myotubes cultured from skeletal muscle biopsies displayed a phase advance after daylight exposure. Multi-omic analyses revealed daylight-induced differences in serum metabolites, lipids, and monocyte transcripts. Our findings suggest that natural daylight exposure has a positive metabolic impact on individuals with type 2 diabetes and could support the treatment of metabolic diseases.
{"title":"Natural daylight during office hours improves glucose control and whole-body substrate metabolism","authors":"Jan-Frieder Harmsen, Ivo Habets, Andrew D. Biancolin, Agata Lesniewska, Nicholas E. Phillips, Loic Metz, Juan Sanchez-Avila, Marit Kotte, Merel Timmermans, Dzhansel Hashim, Soraya S. de Kam, Gert Schaart, Johanna A. Jörgensen, Anne Gemmink, Esther Moonen-Kornips, Daniel Doligkeit, Tineke van de Weijer, Mijke Buitinga, Florian Haans, Rebecca De Lorenzo, Joris Hoeks","doi":"10.1016/j.cmet.2025.11.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.11.006","url":null,"abstract":"Because 80%–90% of our time is spent indoors and daylight is the main synchronizer of the central biological clock, the chronic lack of daylight is increasingly considered as a risk factor for metabolic diseases, such as type 2 diabetes. In a randomized crossover design (NCT05263232), 13 individuals with type 2 diabetes were exposed to natural daylight facilitated through windows vs. constant artificial lighting during office hours for 4.5 consecutive days. Continuous glucose monitoring revealed that participants spent more time in the normal glucose range, and whole-body substrate metabolism shifted toward a greater reliance on fat oxidation during daylight. Primary myotubes cultured from skeletal muscle biopsies displayed a phase advance after daylight exposure. Multi-omic analyses revealed daylight-induced differences in serum metabolites, lipids, and monocyte transcripts. Our findings suggest that natural daylight exposure has a positive metabolic impact on individuals with type 2 diabetes and could support the treatment of metabolic diseases.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"7 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145778081","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}
Pub Date : 2025-12-11DOI: 10.1016/j.cmet.2025.11.010
Alvin P. Chan, Kelsey E. Jarrett, Rochelle W. Lai, Madelaine C. Brearley-Sholto, Angela S. Cheng, Maria O. Taveras, Anne M. Iwata, Michelle E. Steel, Andrew Lau, Emily C. Whang, John P. Kennelly, Yajing Gao, Gabriella E. Rubert, Heidi M. Schmidt, Emily P. Smith, Baolong Su, Kevin J. Williams, Elizabeth J. Tarling, Thomas Q. de Aguiar Vallim
Intestinal lipid absorption, the entry point for fats into the body, requires the coordinated actions of bile acids and lipases. Here, we uncover distinct yet cooperative roles of bile acids in driving the differential uptake of dietary fatty acids. We first decreased the bile acid pool size by disrupting the rate-limiting enzyme in bile acid synthesis, Cyp7a1, using liver-directed gene editing in mice. Compared with lipase inhibition, reduced bile acids prevented diet-induced obesity, increased anorectic hormones, suppressed excessive eating, and improved systemic lipid metabolism. Remarkably, decreasing bile acids selectively reduced the absorption of saturated fatty acids but preserved polyunsaturated fatty acids. By targeting additional bile acid enzymes, we identified specific functions of individual bile acid species. Mechanistically, we show that cholic acid preferentially solubilizes polyunsaturated fatty acids into mixed micelles for intestinal uptake. Our studies demonstrate that bile acids can selectively control fatty acid uptake, revealing insights for future interventions in metabolic diseases.
{"title":"Bile acids regulate lipid metabolism through selective actions on fatty acid absorption","authors":"Alvin P. Chan, Kelsey E. Jarrett, Rochelle W. Lai, Madelaine C. Brearley-Sholto, Angela S. Cheng, Maria O. Taveras, Anne M. Iwata, Michelle E. Steel, Andrew Lau, Emily C. Whang, John P. Kennelly, Yajing Gao, Gabriella E. Rubert, Heidi M. Schmidt, Emily P. Smith, Baolong Su, Kevin J. Williams, Elizabeth J. Tarling, Thomas Q. de Aguiar Vallim","doi":"10.1016/j.cmet.2025.11.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.11.010","url":null,"abstract":"Intestinal lipid absorption, the entry point for fats into the body, requires the coordinated actions of bile acids and lipases. Here, we uncover distinct yet cooperative roles of bile acids in driving the differential uptake of dietary fatty acids. We first decreased the bile acid pool size by disrupting the rate-limiting enzyme in bile acid synthesis, <em>Cyp7a1</em>, using liver-directed gene editing in mice. Compared with lipase inhibition, reduced bile acids prevented diet-induced obesity, increased anorectic hormones, suppressed excessive eating, and improved systemic lipid metabolism. Remarkably, decreasing bile acids selectively reduced the absorption of saturated fatty acids but preserved polyunsaturated fatty acids. By targeting additional bile acid enzymes, we identified specific functions of individual bile acid species. Mechanistically, we show that cholic acid preferentially solubilizes polyunsaturated fatty acids into mixed micelles for intestinal uptake. Our studies demonstrate that bile acids can selectively control fatty acid uptake, revealing insights for future interventions in metabolic diseases.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"10 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728734","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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