Transcriptome analysis of brown fat in young or old mice in cold exposure
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE135391 | GEO | 2020/07/31
REPOSITORIES: GEO
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Project description:Adaptive thermogenesis of brown adipose tissue (BAT) is critical for thermoregulation and contributes to total energy expenditure. However, whether BAT has non-thermogenic functions is largely unknown. Here, we describe that mice with a BAT-specific Liver kinase b1 deletion (Lkb1BKO mice) exhibited impaired mitochondrial respiration and thermogenesis in BAT, but reduced adiposity and liver triglyceride accumulation under high-fat-diet feeding at room temperature. Importantly, these metabolic benefits were also present in Lkb1BKO mice at thermoneutrality, where BAT thermogenesis was not required. Mechanistically, decreased mRNA levels of mtDNA-encoded electron transport chain (ETC) subunits and ETC proteome imbalance led to impaired mitochondrial respiration in BAT of Lkb1BKO mice. Furthermore, reducing mtDNA gene expression directly in BAT by removing mitochondrial transcription factor A (Tfam) in BAT also showed ETC proteome imbalance and the tradeoff between BAT thermogenesis and systemic metabolism at both room temperature and thermoneutrality. Collectively, our data demonstrates that ETC proteome imbalance in BAT regulates systemic metabolism independently of BAT thermogenic capacity.
2018-07-12 | PXD008599 | Pride
Project description:Increasing energy expenditure through activation of brown adipose tissue (BAT) thermogenesis is an attractive approach to counteract obesity. Thus, it is essential to understand molecular mechanisms that control BAT functions. Here, we describe signal transducer and activator of transcription (STAT) 5 as key regulator of BAT functionality. We found that STAT5 is necessary for acute cold-induced temperature maintenance and stimulated lipid breakdown in BAT using mice that harbour an adipocyte-specific deletion of Stat5a/b genes. In addition, the mitochondrial respiratory capacity of primary differentiated brown adipocytes from STAT5 deficient mice was diminished. We show that increased sensitivity to cold stress upon STAT5 deficiency was associated with reduced expression of thermogenic key player uncoupling protein 1, while decreased stimulated lipolysis of STAT5-deficient BAT explants was linked to decreased protein kinase A activity. In addition, brown remodeling of white fat was diminished following chronic β-adrenergic stimulation. This impairment was linked to a decrease in mitochondrial functionality. We conclude that STAT5 is essential for the β-adrenergic responsiveness of brown adipose tissue and the physiologic function of thermogenic adipose tissue.
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Project description:Insufficient mitochondrial quantity in brown adipose tissue (BAT) causes defective thermogenesis and positive energy balance, which is coupled with the development of obesity. Whether disturbance of mitochondrial quality affects BAT function remains unknown. Here, we describe that the brown adipocyte-specific Leucine-rich PPR motif-containing protein knockout mice (LrpprcBKO) exhibited mitochondrial electron transport chain (ETC) proteome imbalance and a complete loss of the -adrenergic-stimulated thermogenesis at room temperature (RT), due to specific reduction of mtDNA-encoded genes. However, the LrpprcBKO mice were lean at normal chow and were protected against high-fat-diet-induced metabolic abnormalities, such as obesity, insulin resistance, adipose inflammation, hepatic steatosis, and hypertriglyceridemia. The beige adipocytes in inguinal white adipose tissue were expanded in LrpprcBKO mice at RT, but not at thermoneutrality. However, BAT thermogenic defects and metabolic benefits were present in LrpprcBKO mice regardless of ambient temperatures. Collectively, our results reveal that a thermogenesis-incapable BAT with mitochondrial ETC proteome imbalance can improve systemic metabolism, suggesting BAT’s contributions to thermoregulation and systemic metabolism can be uncoupled.
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Project description:Brown adipose tissue (BAT) thermogenesis and the browning of white adipose tissue are important components of energy expenditure. An RNAseq-based analysis of the mouse BAT transcriptome led us to identify GPR120 as a gene induced by thermogenic activation. GPR120, a G protein-coupled receptor binding unsaturated long-chain fatty acids, is known to mediate some beneficial metabolic actions of polyunsaturated fatty acids. We show that pharmacological activation of GPR120 induces BAT activity and promotes the browning of white fat in mice, whereas GRP120-null mice show impaired browning in response to cold. n-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF-21) by brown and beige adipocytes and increases blood FGF21 levels. The effects of GPR120 activation are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 constitutes a novel pathway of brown fat activation and involves FGF21.
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Project description:Brown adipose tissue (BAT) is best known for thermogenesis. Whereas numerous studies in rodents found tight associations between the metabolic benefits of BAT and enhanced whole-body energy expenditure, emerging evidence in humans suggests that BAT is protective against Type 2 diabetes independent of body-weight. The underlying mechanism for this dissociation remained unclear. Here, we report that impaired mitochondrial flux of branched-chain amino acids (BCAA) in BAT, by deleting mitochondrial BCAA carrier (MBC, encoded by Slc25a44), was sufficient to cause systemic insulin resistance without affecting whole-body energy expenditure or body-weight. We found that brown adipocytes catabolized BCAAs in the mitochondria as essential nitrogen donors for the biosynthesis of glutamate, N-acetylated amino acids, and one of the products, glutathione. BAT-selective impairment in mitochondrial BCAA flux led to elevated oxidative stress and insulin resistance in the liver, accompanied by reduced levels of BCAA-nitrogen derived metabolites in the circulation. In turn, supplementation of glutathione restored insulin sensitivity of BAT-specific MBC knockout mice. Notably, a high-fat diet rapidly impaired BCAA catabolism and the synthesis of BCAA-nitrogen derived metabolites in the BAT, while cold-induced BAT activity is coupled with an active synthesis of these metabolites. Together, the present work uncovers a mechanism through which brown fat controls metabolic health independent of thermogenesis via BCAA-derived nitrogen carriers acting on the liver.
2024-02-15 | PXD043992 | Pride
Project description:Brown adipose tissue (BAT) is best known for thermogenesis. Whereas numerous studies in rodents found tight associations between the metabolic benefits of BAT and enhanced whole-body energy expenditure, emerging evidence in humans suggests that BAT is protective against Type 2 diabetes independent of body-weight. The underlying mechanism for this dissociation remained unclear. Here, we report that impaired mitochondrial flux of branched-chain amino acids (BCAA) in BAT, by deleting mitochondrial BCAA carrier (MBC, encoded by Slc25a44), was sufficient to cause systemic insulin resistance without affecting whole-body energy expenditure or body-weight. We found that brown adipocytes catabolized BCAAs in the mitochondria as essential nitrogen donors for the biosynthesis of glutamate, N-acetylated amino acids, and one of the products, glutathione. BAT-selective impairment in mitochondrial BCAA flux led to elevated oxidative stress and insulin resistance in the liver, accompanied by reduced levels of BCAA-nitrogen derived metabolites in the circulation. In turn, supplementation of glutathione restored insulin sensitivity of BAT-specific MBC knockout mice. Notably, a high-fat diet rapidly impaired BCAA catabolism and the synthesis of BCAA-nitrogen derived metabolites in the BAT, while cold-induced BAT activity is coupled with an active synthesis of these metabolites. Together, the present work uncovers a mechanism through which brown fat controls metabolic health independent of thermogenesis via BCAA-derived nitrogen carriers acting on the liver.
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Project description:Transcriptional effectors of white adipocyte-selective gene expression have not been described. TLE3 is a white-selective cofactor that acts reciprocally with the brown-selective cofactor Prdm16 to specify lipid storage and thermogenic gene programs. When expressed at elevated levels in brown fat, TLE3 counters Prdm16, suppressing brown-selective genes and inducing white-selective genes, resulting in impaired fatty acid oxidation and thermogenesis. To further test the functional consequences of the changes in BAT phenotype in aP2-TLE3 Tg mice, we challenged them with cold exposure at 4C. aP2-TLE3 Tg mice had an impaired ability to respond to cold exposure compared to littermate control mice, as evidenced by a marked drop in core body temperature. Transgenic mice expressing TLE3 from the aP2 enhancer and wild type mice were housed individually without food and bedding immediately before the start of experiments. Mice were allowed free access to water and placed at 4C for 5 hours while core body temperature was monitored every hour using a rectal probe. For microarray experiments of BAT, RNA was extracted and pooled from 4 mice in each group.
2013-09-27 | E-GEOD-51223 | biostudies-arrayexpress
Project description:In rodents, brown adipose tissue (BAT) contributes to whole body energy expenditure and low BAT activity is related to hepatic fat accumulation, partially attributable to the gut microbiome. Little is known of these relationships in humans. In adults (n=60), we assessed hepatic fat and cold-stimulated BAT activity utilizing magnetic resonance imaging and the gut microbiome with 16S sequencing. We transplanted gnotobiotic mice with feces from humans to assess the transferability of BAT activity and NAFLD through the microbiome. Individuals with NAFLD (n=29) had lower BAT activity than those without and BAT activity was inversely related to hepatic fat. Although the fecal microbiome was different in those with NAFLD, no differences were observed in relation to BAT activity and neither of these phenotypic traits were transmissible through fecal transplant to gnotobiotic mice. Thus, low BAT activity is associated with hepatic steatosis but this is not mediated through the gut microbiota.
2021-09-20 | GSE162608 | GEO
Project description:Transcriptional effectors of white adipocyte-selective gene expression have not been described. TLE3 is a white-selective cofactor that acts reciprocally with the brown-selective cofactor Prdm16 to specify lipid storage and thermogenic gene programs. When expressed at elevated levels in brown fat, TLE3 counters Prdm16, suppressing brown-selective genes and inducing white-selective genes, resulting in impaired fatty acid oxidation and thermogenesis. To further test the functional consequences of the changes in BAT phenotype in aP2-TLE3 Tg mice, we challenged them with cold exposure at 4C. aP2-TLE3 Tg mice had an impaired ability to respond to cold exposure compared to littermate control mice, as evidenced by a marked drop in core body temperature.
2013-09-27 | GSE51223 | GEO