Isocitrate dehydrogenase (IDH) mutations frequently occurr in lower-grade gliomas and secondary glioblastomas. Mutant IDHs exhibit a gain-of-function activity, leading to the production of D-2-hydroxyglutarate (D-2HG) by reducing α-ketoglutarate (α-KG), a central player in metabolism and epigenetic modifications. However, the role of α-KG homeostasis in IDH-mutated gliomagenesis remains elusive. In this study, we found that low expression of oxoglutarate dehydrogenase (OGDH) is a common feature in IDH-mutated gliomas, as well as in astrocytes. This low expression of OGDH results in the accumulation of α-KG and promotes astrocyte maturation. However, IDH1 mutation significantly reduces α-KG levels, and increases glutaminolysis and DNA/histone methylation in astrocytes. These metabolic and epigenetic alterations inhibit astrocyte maturation, and lead to cortical dysplasia in mice. Moreover, our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells, while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation of α-K and increasing glutaminolysis. Finally, we found that L-glutamine increased α-KG levels and augmented the differentiation-promoting effects of AGI5198, an IDH1-mutant inhibitor, in IDH1-mutant glioma cells. Collectively, this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas, providing a potential strategy for the treatment of IDH-mutant gliomas by targeting α-KG homeostasis.
{"title":"IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low OGDH expression by disturbing α-ketoglutarate-related metabolism and epigenetic modification","authors":"Yuanlin Zhao, Ying Yang, Risheng Yang, Chao Sun, Xing Gao, Xiwen Gu, Yuan Yuan, Yating Nie, Shenhui Xu, Ruili Han, Lijun Zhang, Jing Li, P. Hu, Yingmei Wang, Huangtao Chen, Xiangmei Cao, Jing Wu, Zhe Wang, Yu Gu, Jing Ye","doi":"10.1093/lifemeta/loae002","DOIUrl":"https://doi.org/10.1093/lifemeta/loae002","url":null,"abstract":"\u0000 Isocitrate dehydrogenase (IDH) mutations frequently occurr in lower-grade gliomas and secondary glioblastomas. Mutant IDHs exhibit a gain-of-function activity, leading to the production of D-2-hydroxyglutarate (D-2HG) by reducing α-ketoglutarate (α-KG), a central player in metabolism and epigenetic modifications. However, the role of α-KG homeostasis in IDH-mutated gliomagenesis remains elusive. In this study, we found that low expression of oxoglutarate dehydrogenase (OGDH) is a common feature in IDH-mutated gliomas, as well as in astrocytes. This low expression of OGDH results in the accumulation of α-KG and promotes astrocyte maturation. However, IDH1 mutation significantly reduces α-KG levels, and increases glutaminolysis and DNA/histone methylation in astrocytes. These metabolic and epigenetic alterations inhibit astrocyte maturation, and lead to cortical dysplasia in mice. Moreover, our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells, while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation of α-K and increasing glutaminolysis. Finally, we found that L-glutamine increased α-KG levels and augmented the differentiation-promoting effects of AGI5198, an IDH1-mutant inhibitor, in IDH1-mutant glioma cells. Collectively, this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas, providing a potential strategy for the treatment of IDH-mutant gliomas by targeting α-KG homeostasis.","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139528755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-09DOI: 10.1093/lifemeta/load049
Xiaoli Ma, Hong Zhang
{"title":"Join the club: YIPF3 and YIPF4 act as Golgiphagy receptors","authors":"Xiaoli Ma, Hong Zhang","doi":"10.1093/lifemeta/load049","DOIUrl":"https://doi.org/10.1093/lifemeta/load049","url":null,"abstract":"","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138585775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-11-18DOI: 10.1093/lifemeta/load042
Yuelong Yan, Boyi Gan
The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application. A recent study published in Molecular Cell has identified hyperoxidized peroxiredoxin 3 (PRDX3) as a promising marker for ferroptosis, opening up new avenues for monitoring and targeting ferroptosis in disease treatment.
{"title":"Hyperoxidized PRDX3 as a specific ferroptosis marker.","authors":"Yuelong Yan, Boyi Gan","doi":"10.1093/lifemeta/load042","DOIUrl":"10.1093/lifemeta/load042","url":null,"abstract":"<p><p>The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application. A recent study published in <i>Molecular Cell</i> has identified hyperoxidized peroxiredoxin 3 (PRDX3) as a promising marker for ferroptosis, opening up new avenues for monitoring and targeting ferroptosis in disease treatment.</p>","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10766428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139099341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1093/lifemeta/load047
Xiuxiu Liu, Bin Zhou
The metabolic state of a cell is closely related to its structure and function in adult mammalian cardiomyocytes. These adult cardiomyocytes primarily use fatty acids as an energy substrate to support heart contraction. Recently, Li and his colleagues reported that inhibiting fatty acid oxidation in cardiomyocytes keeps them in an immature state. This influences epigenomic modifications and ultimately increases the proliferation capacity of the cardiomyocytes.
{"title":"Metabolic restraining of epigenetic modifications promotes cardiomyocyte proliferation","authors":"Xiuxiu Liu, Bin Zhou","doi":"10.1093/lifemeta/load047","DOIUrl":"https://doi.org/10.1093/lifemeta/load047","url":null,"abstract":"\u0000 The metabolic state of a cell is closely related to its structure and function in adult mammalian cardiomyocytes. These adult cardiomyocytes primarily use fatty acids as an energy substrate to support heart contraction. Recently, Li and his colleagues reported that inhibiting fatty acid oxidation in cardiomyocytes keeps them in an immature state. This influences epigenomic modifications and ultimately increases the proliferation capacity of the cardiomyocytes.","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138625844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-27DOI: 10.1093/lifemeta/load046
David Sokolov, Lucas B Sullivan
In addition to their canonical roles in biosynthetic pathways, metabolites can be active participants in oncogenic signaling, but our understanding of these signaling mechanisms is incomplete. In a recent article published in Cell, Mossmann and colleagues find a novel signaling role for accumulated arginine in hepatocellular carcinoma (HCC), mediated by the RNA splicing factor and transcriptional modifier RNA-binding protein 39 (RBM39).
{"title":"A metabolic signaling role for arginine in liver cancer","authors":"David Sokolov, Lucas B Sullivan","doi":"10.1093/lifemeta/load046","DOIUrl":"https://doi.org/10.1093/lifemeta/load046","url":null,"abstract":"In addition to their canonical roles in biosynthetic pathways, metabolites can be active participants in oncogenic signaling, but our understanding of these signaling mechanisms is incomplete. In a recent article published in Cell, Mossmann and colleagues find a novel signaling role for accumulated arginine in hepatocellular carcinoma (HCC), mediated by the RNA splicing factor and transcriptional modifier RNA-binding protein 39 (RBM39).","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139230477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-21DOI: 10.1093/lifemeta/load044
Tiange Feng, Yuan Liang, Lijun Sun, Lu Feng, Jiajie Min, Michael W Mulholland, Yue Yin, Weizhen Zhang
The “gut-liver axis” is critical for the control of hepatic lipid homeostasis, where the intestine affects the liver through multiple pathways such as nutrient uptake, gastrointestinal hormone release, and gut microbiota homeostasis. Whether intestine-originated exosomes mediate the gut’s influence on liver steatosis remains unknown. Here we aimed to determine whether intestinal epithelium-derived exosomes (intExos) contribute to the regulation of hepatic lipid metabolism. We found that mouse intExos could be taken up by hepatic cells. Mice fed high-fat diet (HFD) received intExos showed strong resistance to liver steatosis. MicroRNA sequencing of intExos indicated the correlation between miR-21a-5p/miR-145a-5p and hepatic lipid metabolism. Both liver overexpression of miR-21a-5p and intExos containing miR-21a-5p alleviated hepatic steatosis in mice fed with HFD. Mechanistically, miR-21a-5p suppressed the expression of Ccl1 (C-C motif chemokine ligand 1) in macrophages, as well as lipid transport genes Cd36 (cluster of differentiation 36) and Fabp7 (fatty acid binding protein 7) in hepatocytes. Liver-specific inhibition of miR-145a-5p significantly reduced hepatic lipid accumulation in mice fed with HFD through negatively regulating the expression of Btg1 (BTG anti-proliferation factor 1), leading to an increase of stearoyl-CoA desaturase-1 and lipogenesis.Our study demonstrates that intExos regulate hepatic lipid metabolism and NAFLD (non-alcoholic fatty liver disease) progression via miR-21a-5p and miR-145a-5p pathways, providing novel mediators for the gut-liver crosstalk and potential targets for regulating hepatic lipid metabolism.
{"title":"Regulation of hepatic lipid metabolism by intestine epithelium-derived exosomes","authors":"Tiange Feng, Yuan Liang, Lijun Sun, Lu Feng, Jiajie Min, Michael W Mulholland, Yue Yin, Weizhen Zhang","doi":"10.1093/lifemeta/load044","DOIUrl":"https://doi.org/10.1093/lifemeta/load044","url":null,"abstract":"The “gut-liver axis” is critical for the control of hepatic lipid homeostasis, where the intestine affects the liver through multiple pathways such as nutrient uptake, gastrointestinal hormone release, and gut microbiota homeostasis. Whether intestine-originated exosomes mediate the gut’s influence on liver steatosis remains unknown. Here we aimed to determine whether intestinal epithelium-derived exosomes (intExos) contribute to the regulation of hepatic lipid metabolism. We found that mouse intExos could be taken up by hepatic cells. Mice fed high-fat diet (HFD) received intExos showed strong resistance to liver steatosis. MicroRNA sequencing of intExos indicated the correlation between miR-21a-5p/miR-145a-5p and hepatic lipid metabolism. Both liver overexpression of miR-21a-5p and intExos containing miR-21a-5p alleviated hepatic steatosis in mice fed with HFD. Mechanistically, miR-21a-5p suppressed the expression of Ccl1 (C-C motif chemokine ligand 1) in macrophages, as well as lipid transport genes Cd36 (cluster of differentiation 36) and Fabp7 (fatty acid binding protein 7) in hepatocytes. Liver-specific inhibition of miR-145a-5p significantly reduced hepatic lipid accumulation in mice fed with HFD through negatively regulating the expression of Btg1 (BTG anti-proliferation factor 1), leading to an increase of stearoyl-CoA desaturase-1 and lipogenesis.Our study demonstrates that intExos regulate hepatic lipid metabolism and NAFLD (non-alcoholic fatty liver disease) progression via miR-21a-5p and miR-145a-5p pathways, providing novel mediators for the gut-liver crosstalk and potential targets for regulating hepatic lipid metabolism.","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139250806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-21DOI: 10.1093/lifemeta/load045
Limin Xie, Wanyu Hu, Haowei Zhang, Yujin Ding, Qin Zeng, Xiyan Liao, Dandan Wang, Wanqin Xie, Xiaoyan Hui, Tuo Deng
Regardless of its anatomical site, adipose tissue shares a common energy-storage role but exhibits distinctive properties. Exploring the cellular and molecular heterogeneity of white adipose tissue (WAT) is crucial for comprehending its function and properties. However, existing single-nucleus RNA sequencing (snRNA-seq) studies of adipose tissue heterogeneity have examined only one or two depots. In this study, we employed snRNA-seq to test five representative depots including inguinal, epididymal, mesenteric, perirenal, and pericardial adipose tissues in mice under physiological conditions. By analyzing the contents of main cell categories and gene profiles of various depots, we identified their distinctive physiological properties. Immune cells and fibro-adipogenic progenitor cells (FAPs) showed dramatic differences among WAT depots, while adipocytes seemed to be conserved. The heightened presence of regulatory macrophages and B cells in pericardial adipose tissues implied their potential contribution to the preservation of coronary vascular function. Moreover, the selective aggregation of pericytes within mesenteric adipose tissue was likely associated with the maintenance of intestinal barrier homeostasis. Using a combination of RNA sequencing and snRNA-seq analysis, the major subpopulations of FAPs derived from these depots determined the site characteristics of FAPs to a certain extent. Our work establishes a systematic and reliable foundation for investigating the heterogeneity of WAT depots and elucidating the unique roles these depots play in coordinating the function of adjacent organs.
无论解剖部位如何，脂肪组织都有一个共同的储能作用，但却表现出与众不同的特性。探索白色脂肪组织（WAT）的细胞和分子异质性对于理解其功能和特性至关重要。然而，现有的关于脂肪组织异质性的单核 RNA 测序（snRNA-seq）研究只考察了一个或两个脂肪库。在本研究中，我们采用 snRNA-seq 技术检测了生理条件下小鼠腹股沟、附睾、肠系膜、肾周和心包等五个代表性脂肪组织。通过分析不同脂肪组织的主要细胞类别和基因谱，我们确定了它们各自不同的生理特性。免疫细胞和纤维-成脂祖细胞（FAPs）在不同的脂肪组织中显示出巨大的差异，而脂肪细胞似乎是一致的。调节性巨噬细胞和 B 细胞在心包脂肪组织中的高度存在意味着它们对冠状动脉血管功能的保护具有潜在的贡献。此外，肠系膜脂肪组织中的周细胞选择性聚集可能与肠屏障稳态的维持有关。利用RNA测序和snRNA-seq分析相结合的方法，从这些储层中提取的FAPs主要亚群在一定程度上确定了FAPs的部位特征。我们的工作为研究 WAT 储库的异质性和阐明这些储库在协调相邻器官功能方面的独特作用奠定了系统而可靠的基础。
{"title":"Single-nucleus RNA sequencing reveals heterogeneity among multiple white adipose tissue depots","authors":"Limin Xie, Wanyu Hu, Haowei Zhang, Yujin Ding, Qin Zeng, Xiyan Liao, Dandan Wang, Wanqin Xie, Xiaoyan Hui, Tuo Deng","doi":"10.1093/lifemeta/load045","DOIUrl":"https://doi.org/10.1093/lifemeta/load045","url":null,"abstract":"Regardless of its anatomical site, adipose tissue shares a common energy-storage role but exhibits distinctive properties. Exploring the cellular and molecular heterogeneity of white adipose tissue (WAT) is crucial for comprehending its function and properties. However, existing single-nucleus RNA sequencing (snRNA-seq) studies of adipose tissue heterogeneity have examined only one or two depots. In this study, we employed snRNA-seq to test five representative depots including inguinal, epididymal, mesenteric, perirenal, and pericardial adipose tissues in mice under physiological conditions. By analyzing the contents of main cell categories and gene profiles of various depots, we identified their distinctive physiological properties. Immune cells and fibro-adipogenic progenitor cells (FAPs) showed dramatic differences among WAT depots, while adipocytes seemed to be conserved. The heightened presence of regulatory macrophages and B cells in pericardial adipose tissues implied their potential contribution to the preservation of coronary vascular function. Moreover, the selective aggregation of pericytes within mesenteric adipose tissue was likely associated with the maintenance of intestinal barrier homeostasis. Using a combination of RNA sequencing and snRNA-seq analysis, the major subpopulations of FAPs derived from these depots determined the site characteristics of FAPs to a certain extent. Our work establishes a systematic and reliable foundation for investigating the heterogeneity of WAT depots and elucidating the unique roles these depots play in coordinating the function of adjacent organs.","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139252397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-15DOI: 10.1093/lifemeta/load043
O. K. Fuller, Casey L. Egan, Tina L Robinson, Nimna Perera, Heidy K Latchman, Lauren V Terry, Emma D. McLennan, Carolina Chavez, Emma L. Burrows, John W Scott, Robyn M Murphy, H. van Praag, M. Whitham, M. Febbraio
Obesity has been linked to a range of pathologies, including dementia. In contrast, regular physical activity is associated with the prevention or reduced progression of neurodegeneration. Specifically, physical activity can improve memory and spatial cognition, reduce age-related cognitive decline, and preserve brain volume, but the mechanisms are not fully understood. Accordingly, we investigated whether any detrimental effects of high-fat diet (HFD)-induced obesity on cognition, motor behavior, adult hippocampal neurogenesis, and brain-derived neurotrophic factor (BDNF) could be mitigated by voluntary exercise training in male C57Bl/6 mice. HFD-induced impairment of motor function was not reversed by exercise. Importantly, voluntary wheel running improved long-term memory and increased hippocampal neurogenesis, suggesting that regular physical activity may prevent cognitive decline in obesity.
{"title":"Exercise training improves long-term memory in obese mice","authors":"O. K. Fuller, Casey L. Egan, Tina L Robinson, Nimna Perera, Heidy K Latchman, Lauren V Terry, Emma D. McLennan, Carolina Chavez, Emma L. Burrows, John W Scott, Robyn M Murphy, H. van Praag, M. Whitham, M. Febbraio","doi":"10.1093/lifemeta/load043","DOIUrl":"https://doi.org/10.1093/lifemeta/load043","url":null,"abstract":"Obesity has been linked to a range of pathologies, including dementia. In contrast, regular physical activity is associated with the prevention or reduced progression of neurodegeneration. Specifically, physical activity can improve memory and spatial cognition, reduce age-related cognitive decline, and preserve brain volume, but the mechanisms are not fully understood. Accordingly, we investigated whether any detrimental effects of high-fat diet (HFD)-induced obesity on cognition, motor behavior, adult hippocampal neurogenesis, and brain-derived neurotrophic factor (BDNF) could be mitigated by voluntary exercise training in male C57Bl/6 mice. HFD-induced impairment of motor function was not reversed by exercise. Importantly, voluntary wheel running improved long-term memory and increased hippocampal neurogenesis, suggesting that regular physical activity may prevent cognitive decline in obesity.","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139273321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-06DOI: 10.1093/lifemeta/load041
Shuo Wang, Lingling Zhang, Jingyu Zhao, Meijuan Bai, Yijun Lin, Qianqian Chu, Jue Gong, Ju Qiu, Yan Chen
Abstract The monocarboxylate transporter 1 (MCT1), encoded by gene Slc16a1, is a proton-coupled transporter for lactate and other monocarboxylates. MCT1-mediated lactate transport was recently found to regulate various biological functions. However, how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is unclear. In this study, we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium (Slc16a1IKO mice) and investigated the functions of MCT1 in the gut. When fed a high-fat diet, Slc16a1IKO male mice had improvement in glucose tolerance and insulin sensitivity, while Slc16a1IKO female mice only had increased adiposity. Deficiency of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways, together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha (TNFα) and C-C motif chemokine ligand 2 (CCL2). Lactate had a stimulatory effect on pro-inflammatory macrophages in vitro. The number of intestinal macrophages was reduced in Slc16a1IKO male mice in vivo. Intestinal deletion of Slc16a1 in male mice reduced interstitial lactate level in the intestine. In addition, treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference of glucose homeostasis between Slc16a1IKO and wild-type mice. Deficiency of intestinal MCT1 also blocked transport of lactate and short-chain fatty acids from the intestine to the portal vein. The effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut microbiota. In conclusion, our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.
{"title":"Intestinal monocarboxylate transporter 1 mediates lactate transport in the gut and regulates metabolic homeostasis of mouse in a sex-dimorphic pattern","authors":"Shuo Wang, Lingling Zhang, Jingyu Zhao, Meijuan Bai, Yijun Lin, Qianqian Chu, Jue Gong, Ju Qiu, Yan Chen","doi":"10.1093/lifemeta/load041","DOIUrl":"https://doi.org/10.1093/lifemeta/load041","url":null,"abstract":"Abstract The monocarboxylate transporter 1 (MCT1), encoded by gene Slc16a1, is a proton-coupled transporter for lactate and other monocarboxylates. MCT1-mediated lactate transport was recently found to regulate various biological functions. However, how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is unclear. In this study, we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium (Slc16a1IKO mice) and investigated the functions of MCT1 in the gut. When fed a high-fat diet, Slc16a1IKO male mice had improvement in glucose tolerance and insulin sensitivity, while Slc16a1IKO female mice only had increased adiposity. Deficiency of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways, together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha (TNFα) and C-C motif chemokine ligand 2 (CCL2). Lactate had a stimulatory effect on pro-inflammatory macrophages in vitro. The number of intestinal macrophages was reduced in Slc16a1IKO male mice in vivo. Intestinal deletion of Slc16a1 in male mice reduced interstitial lactate level in the intestine. In addition, treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference of glucose homeostasis between Slc16a1IKO and wild-type mice. Deficiency of intestinal MCT1 also blocked transport of lactate and short-chain fatty acids from the intestine to the portal vein. The effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut microbiota. In conclusion, our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135685209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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