Heme Biosynthesis Regulates BCAA Catabolism and Thermogenesis in Brown Adipose Tissue
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ABSTRACT:
PROVIDER: PRJNA1222362 | ENA |
REPOSITORIES: ENA
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Project description:The distinctive color of brown adipose tissue (BAT) is attributed to its high content of heme-rich mitochondria. Despite this, the mechanisms by which BAT regulates intracellular heme levels remain largely unexplored. Here, we demonstrate that heme biosynthesis is the primary source of heme in brown adipocytes. Inhibiting heme biosynthesis results in an accumulation of the branched-chain amino acids (BCAAs) valine and isoleucine, due to a heme-associated metabolon that channels BCAA-derived carbons into heme biosynthesis. Heme synthesis-deficient brown adipocytes display reduced mitochondrial respiration and lower UCP1 levels compared to wild-type cells. While exogenous heme supplementation can restore intracellular heme levels and mitochondrial function, UCP1 downregulation persists. This sustained UCP1 suppression is linked to epigenetic regulation induced by the accumulation of propionyl-CoA, a byproduct of disrupted heme synthesis. Finally, disruption of heme biosynthesis in BAT impairs thermogenic response and, in female, but not male, mice, hinders the cold- induced clearance of circulating BCAAs in a sex-hormone-dependent manner. These findings establish adipose heme biosynthesis as a key regulator of thermogenesis and sex-dependent BCAA homeostasis.
2025-02-18 | GSE289295 | GEO
Project description:The distinctive color of brown adipose tissue (BAT) is attributed to its high content of heme-rich mitochondria. Despite this, the mechanisms by which BAT regulates intracellular heme levels remain largely unexplored. Here, we demonstrate that heme biosynthesis is the primary source of heme in brown adipocytes. Inhibiting heme biosynthesis results in an accumulation of the branched-chain amino acids (BCAAs) valine and isoleucine, due to a heme-associated metabolon that channels BCAA-derived carbons into heme biosynthesis. Heme synthesis-deficient brown adipocytes display reduced mitochondrial respiration and lower UCP1 levels compared to wild-type cells. While exogenous heme supplementation can restore intracellular heme levels and mitochondrial function, downregulation persists. This sustained UCP1 suppression is linked to epigenetic regulation induced by the accumulation of propionyl-CoA, a byproduct of disrupted heme synthesis. Finally, disruption of heme biosynthesis in BAT impairs thermogenic response and, in female, but not male, mice, hinders the cold- induced clearance of circulating BCAAs in a sex-hormone-dependent manner. These findings establish adipose heme biosynthesis as a key regulator of thermogenesis and sex-dependent BCAA homeostasis.
2025-02-17 | PXD060812 | 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.
2024-02-15 | PXD044020 | 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.
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 wholebody 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-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.
2024-03-05 | PXD043813 | JPOST Repository
Project description:We used RNA-Seq to ask whether the transcripts for the proposed BCKDH subunits are upregulated in wild-type plants subjected to prolonged darkness. These experiments were performed using rosette leaves from 5-week-old, short-day-grown (8h light/16h dark) Col-0 wild-type plants moved to constant darkness for 6h, 24h, 48h and 72h, and grown in short day for 72h as control. The transcripts of eight BCAA catabolism genes were increased nine- to 400-fold within the first 6h of prolonged darkness, and remained high until the last time point. These results are consistent with the hypothesis that BCAA catabolic enzymes - including BCKDH subunits E1A1, E1B1, E1B2 and E2 - have one or more physiological roles in the dark. Rosette leaf mRNA profiles of 5-week old Col wild type (WT, CS60000) and BCAA catabolic mutants ivd1-2 and hml1-2 were generated byRNA sequencing, in duplicate, using Illumina HiSeq2500.
2015-04-16 | E-GEOD-67956 | biostudies-arrayexpress
Project description:Impaired branched-chain amino acid (BCAA) catabolism has recently been implicated in the development of mechanical pain, but the underlying molecular mechanisms are unclear. Here we report that defective BCAA catabolism in dorsal root ganglion (DRG) neurons sensitizes mice to mechanical pain by increasing lactate production and expression of the mechanotransduction channel Piezo2. In high-fat diet-fed obese mice, we observe downregulation of PP2Cm, a key regulator of the BCAA catabolic pathway, in DRG neurons. Mice with conditional knockout of PP2Cm in DRG neurons exhibit mechanical allodynia under normal or SNI-induced neuropathic injury conditions. Furthermore, the VAS scores in the plasma of patients with peripheral neuropathic pain are positively correlated with BCAA contents. Mechanistically, defective BCAA catabolism in DRG neurons promotes lactate production through glycolysis, which increases H3K18la modification and drives Piezo2 expression. Inhibition of lactate production or Piezo2 silencing attenuates the pain phenotype of knockout mice in response to mechanical stimuli. Therefore, our study demonstrates a causal role of defective BCAA catabolism in mechanical pain by enhancing metabolite-mediated epigenetic regulation.
2023-08-27 | GSE235230 | GEO
Project description:Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.
| S-EPMC6715529 | biostudies-literature
Project description:PROX1 Orchestrates Tumor Metabolic Plasticity by Integrating LKB1-AMPK Signaling with BCAA Catabolism
| PRJNA884334 | ENA
Project description:We used RNA-Seq to ask whether the transcripts for the proposed BCKDH subunits are upregulated in wild-type plants subjected to prolonged darkness. These experiments were performed using rosette leaves from 5-week-old, short-day-grown (8h light/16h dark) Col-0 wild-type plants moved to constant darkness for 6h, 24h, 48h and 72h, and grown in short day for 72h as control. The transcripts of eight BCAA catabolism genes were increased nine- to 400-fold within the first 6h of prolonged darkness, and remained high until the last time point. These results are consistent with the hypothesis that BCAA catabolic enzymes - including BCKDH subunits E1A1, E1B1, E1B2 and E2 - have one or more physiological roles in the dark.
2015-04-16 | GSE67956 | GEO