{"title":"Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells","authors":"Jing-Lin Liu, Xu Xu, Youlutuziayi Rixiati, Chu-Yi Wang, Heng-Li Ni, Wen-Shu Chen, Hui-Min Gong, Zi-Long Zhang, Shi Li, Tong Shen, Jian-Ming Li","doi":"10.1016/j.cmet.2024.04.019","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.04.019","url":null,"abstract":"<p>Circadian homeostasis in mammals is a key intrinsic mechanism for responding to the external environment. However, the interplay between circadian rhythms and the tumor microenvironment (TME) and its influence on metastasis are still unclear. Here, in patients with colorectal cancer (CRC), disturbances of circadian rhythm and the accumulation of monocytes and granulocytes were closely related to metastasis. Moreover, dysregulation of circadian rhythm promoted lung metastasis of CRC by inducing the accumulation of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8<sup>+</sup> T cells in the lungs of mice. Also, gut microbiota and its derived metabolite taurocholic acid (TCA) contributed to lung metastasis of CRC by triggering the accumulation of MDSCs in mice. Mechanistically, TCA promoted glycolysis of MDSCs epigenetically by enhancing mono-methylation of H3K4 of target genes and inhibited CHIP-mediated ubiquitination of PDL1. Our study links the biological clock with MDSCs in the TME through gut microbiota/metabolites in controlling the metastatic spread of CRC, uncovering a systemic mechanism for cancer metastasis.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246352","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 browning and mobilization of subcutaneous white adipose tissue supports efficient skin repair","authors":"Junrong Cai, Yuping Quan, Shaowei Zhu, , Qian Zhang, Juzi Liu, Zhuokai Liang, Yunjun Liao, Wenqing Jiang, Yufei He, Ting Su, Feng Lu","doi":"10.1016/j.cmet.2024.05.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.05.005","url":null,"abstract":"<p>Adipocytes in dermis are considered to be important participants in skin repair and regeneration, but the role of subcutaneous white adipose tissue (sWAT) in skin repair is poorly understood. Here, we revealed the dynamic changes of sWAT during wound healing process. Lineage-tracing mouse studies revealed that sWAT would enter into the large wound bed and participate in the formation of granulation tissue. Moreover, sWAT undergoes beiging after skin injury. Inhibition of sWAT beiging by genetically silencing PRDM16, a key regulator to beiging, hindered wound healing process. The transcriptomics results suggested that beige adipocytes in sWAT abundantly express neuregulin 4 (NRG4), which regulated macrophage polarization and the function of myofibroblasts. In diabetic wounds, the beiging of sWAT was significantly suppressed. Thus, adipocytes from sWAT regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246297","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 : 2024-06-04DOI: 10.1016/j.cmet.2024.05.002
Isaac Marin-Valencia, Arif Kocabas, Carlos Rodriguez-Navas, Vesselin Z. Miloushev, Manuel González-Rodríguez, Hannah Lees, Kelly E. Henry, Jake Vaynshteyn, Valerie Longo, Kofi Deh, Roozbeh Eskandari, Arsen Mamakhanyan, Marjan Berishaj, Kayvan R. Keshari
{"title":"Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency","authors":"Isaac Marin-Valencia, Arif Kocabas, Carlos Rodriguez-Navas, Vesselin Z. Miloushev, Manuel González-Rodríguez, Hannah Lees, Kelly E. Henry, Jake Vaynshteyn, Valerie Longo, Kofi Deh, Roozbeh Eskandari, Arsen Mamakhanyan, Marjan Berishaj, Kayvan R. Keshari","doi":"10.1016/j.cmet.2024.05.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.05.002","url":null,"abstract":"<p>A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease <em>in vivo</em>. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, <em>in vivo</em> brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain—it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246267","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 : 2024-06-04DOI: 10.1016/j.cmet.2024.04.020
Wei Xie, Jing Gan, Xiaodong Zhou, Huiying Tian, Xingchao Pan, Wenyue Liu, Xiaokun Li, Jie Du, Aimin Xu, Minghua Zheng, Fan Wu, Yuling Li, Zhuofeng Lin
{"title":"Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti","authors":"Wei Xie, Jing Gan, Xiaodong Zhou, Huiying Tian, Xingchao Pan, Wenyue Liu, Xiaokun Li, Jie Du, Aimin Xu, Minghua Zheng, Fan Wu, Yuling Li, Zhuofeng Lin","doi":"10.1016/j.cmet.2024.04.020","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.04.020","url":null,"abstract":"<p>Patients with metabolic dysfunction-associated steatotic liver disease (MASLD), especially advanced metabolic dysfunction-associated steatohepatitis (MASH), have an increased risk of cardiovascular diseases (CVDs). Whether CVD events will, in turn, influence the pathogenesis of MASLD remains unknown. Here, we show that myocardial infarction (MI) accelerates hepatic pathological progression of MASLD. Patients with MASLD who experience CVD events after their diagnosis exhibit accelerated liver fibrosis progression. MI promotes hepatic fibrosis in mice with MASH, accompanied by elevated circulating Ly6C<sup>hi</sup> monocytes and their recruitment to damaged liver tissues. These adverse effects are significantly abrogated when deleting these cells. Meanwhile, MI substantially increases circulating and cardiac periostin levels, which act on hepatocytes and stellate cells to promote hepatic lipid accumulation and fibrosis, finally exacerbating hepatic pathological progression of MASH. These preclinical and clinical results demonstrate that MI alters systemic homeostasis and upregulates pro-fibrotic factor production, triggering cross-disease communication that accelerates hepatic pathological progression of MASLD.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246314","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 : 2024-06-04DOI: 10.1016/j.cmet.2024.05.001
Moufida Ben Nasr, Vera Usuelli, Sergio Dellepiane, Andy Joe Seelam, Teresa Vanessa Fiorentino, Francesca D’Addio, Emma Fiorina, Cong Xu, Yanan Xie, Hari Baskar Balasubramanian, Eduardo Castillo-Leon, Lara Loreggian, Anna Maestroni, Emma Assi, Cristian Loretelli, Ahmed Abdelsalam, Basset El Essawy, Silvia Uccella, Ida Pastore, Maria Elena Lunati, Paolo Fiorina
{"title":"Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule","authors":"Moufida Ben Nasr, Vera Usuelli, Sergio Dellepiane, Andy Joe Seelam, Teresa Vanessa Fiorentino, Francesca D’Addio, Emma Fiorina, Cong Xu, Yanan Xie, Hari Baskar Balasubramanian, Eduardo Castillo-Leon, Lara Loreggian, Anna Maestroni, Emma Assi, Cristian Loretelli, Ahmed Abdelsalam, Basset El Essawy, Silvia Uccella, Ida Pastore, Maria Elena Lunati, Paolo Fiorina","doi":"10.1016/j.cmet.2024.05.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.05.001","url":null,"abstract":"<p>Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic β cells. We herein investigated the role of GLP-1R on T lymphocytes during immune response. Our data showed that a subset of T lymphocytes expresses GLP-1R, which is upregulated during alloimmune response, similarly to PD-1. When mice received islet or cardiac allotransplantation, an expansion of GLP-1R<sup>pos</sup> T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA sequencing (scRNA-seq) analysis conducted on GLP-1R<sup>pos</sup> and GLP-1R<sup>neg</sup> CD3<sup>+</sup> T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1R<sup>pos</sup> are mainly composed of exhausted CD8 T cells. GLP-1R acts as a T cell-negative costimulatory molecule, and GLP-1R signaling prolongs allograft survival, mitigates alloimmune response, and reduces T lymphocyte graft infiltration. Notably, GLP-1R antagonism triggered anti-tumor immunity when tested in a preclinical mouse model of colorectal cancer.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246364","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 : 2024-06-03DOI: 10.1016/j.cmet.2024.05.006
Elaine Zaunseder, Ulrike Mütze, Jürgen G. Okun, Georg F. Hoffmann, Stefan Kölker, Vincent Heuveline, Ines Thiele
{"title":"Personalized metabolic whole-body models for newborns and infants predict growth and biomarkers of inherited metabolic diseases","authors":"Elaine Zaunseder, Ulrike Mütze, Jürgen G. Okun, Georg F. Hoffmann, Stefan Kölker, Vincent Heuveline, Ines Thiele","doi":"10.1016/j.cmet.2024.05.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.05.006","url":null,"abstract":"<p>Comprehensive whole-body models (WBMs) accounting for organ-specific dynamics have been developed to simulate adult metabolism, but such models do not exist for infants. Here, we present a resource of 360 organ-resolved, sex-specific models of newborn and infant metabolism (infant-WBMs) spanning the first 180 days of life. These infant-WBMs were parameterized to represent the distinct metabolic characteristics of newborns and infants, including nutrition, energy requirements, and thermoregulation. We demonstrate that the predicted infant growth was consistent with the recommendation by the World Health Organization. We assessed the infant-WBMs’ reliability and capabilities for personalization by simulating 10,000 newborns based on their blood metabolome and birth weight. Furthermore, the infant-WBMs accurately predicted changes in known biomarkers over time and metabolic responses to treatment strategies for inherited metabolic diseases. The infant-WBM resource holds promise for personalized medicine, as the infant-WBMs could be a first step to digital metabolic twins for newborn and infant metabolism.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246358","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 : 2024-05-31DOI: 10.1016/j.cmet.2024.05.003
Paul Horn, Frank Tacke
{"title":"Metabolic reprogramming in liver fibrosis","authors":"Paul Horn, Frank Tacke","doi":"10.1016/j.cmet.2024.05.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.05.003","url":null,"abstract":"<p>Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141182650","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 : 2024-05-20DOI: 10.1016/j.cmet.2024.04.018
Fei Peng, Jinxin Lu, Keyu Su, Xinyu Liu, Huandong Luo, Bin He, Cenxin Wang, Xiaoyu Zhang, Fan An, Dekang Lv, Yuanyuan Luo, Qitong Su, Tonghui Jiang, Ziqian Deng, Bin He, Lingzhi Xu, Tao Guo, Jin Xiang, Chundong Gu, Ling Wang, Quentin Liu
{"title":"Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis","authors":"Fei Peng, Jinxin Lu, Keyu Su, Xinyu Liu, Huandong Luo, Bin He, Cenxin Wang, Xiaoyu Zhang, Fan An, Dekang Lv, Yuanyuan Luo, Qitong Su, Tonghui Jiang, Ziqian Deng, Bin He, Lingzhi Xu, Tao Guo, Jin Xiang, Chundong Gu, Ling Wang, Quentin Liu","doi":"10.1016/j.cmet.2024.04.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.04.018","url":null,"abstract":"<p>Circadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed β-endorphin resets rhythmic <em>Clock</em> and <em>Acsl1</em> expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum β-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented β-endorphin as a potential chronotherapeutic strategy for SD-related cancer.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069216","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 : 2024-05-09DOI: 10.1016/j.cmet.2024.04.017
Radiana Ferrero, Pernille Yde Rainer, Marie Rumpler, Julie Russeil, Magda Zachara, Joern Pezoldt, Guido van Mierlo, Vincent Gardeux, Wouter Saelens, Daniel Alpern, Lucie Favre, Nathalie Vionnet, Styliani Mantziari, Tobias Zingg, Nelly Pitteloud, Michel Suter, Maurice Matter, Kai-Uwe Schlaudraff, Carles Canto, Bart Deplancke
{"title":"A human omentum-specific mesothelial-like stromal population inhibits adipogenesis through IGFBP2 secretion","authors":"Radiana Ferrero, Pernille Yde Rainer, Marie Rumpler, Julie Russeil, Magda Zachara, Joern Pezoldt, Guido van Mierlo, Vincent Gardeux, Wouter Saelens, Daniel Alpern, Lucie Favre, Nathalie Vionnet, Styliani Mantziari, Tobias Zingg, Nelly Pitteloud, Michel Suter, Maurice Matter, Kai-Uwe Schlaudraff, Carles Canto, Bart Deplancke","doi":"10.1016/j.cmet.2024.04.017","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.04.017","url":null,"abstract":"<p>Adipose tissue plasticity is orchestrated by molecularly and functionally diverse cells within the stromal vascular fraction (SVF). Although several mouse and human adipose SVF cellular subpopulations have by now been identified, we still lack an understanding of the cellular and functional variability of adipose stem and progenitor cell (ASPC) populations across human fat depots. To address this, we performed single-cell and bulk RNA sequencing (RNA-seq) analyses of >30 SVF/Lin− samples across four human adipose depots, revealing two ubiquitous human ASPC (hASPC) subpopulations with distinct proliferative and adipogenic properties but also depot- and BMI-dependent proportions. Furthermore, we identified an omental-specific, high <em>IGFBP2-</em>expressing stromal population that transitions between mesothelial and mesenchymal cell states and inhibits hASPC adipogenesis through IGFBP2 secretion. Our analyses highlight the molecular and cellular uniqueness of different adipose niches, while our discovery of an anti-adipogenic IGFBP2+ omental-specific population provides a new rationale for the biomedically relevant, limited adipogenic capacity of omental hASPCs.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140895895","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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