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Uncoupling Metabolic Health from Thermogenesis via BCAA Flux in Brown Fat

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brown Adipose Tissue

SUBMITTER: Anthony Verkerke

LAB HEAD: Shingo Kajimura

PROVIDER: PXD043992 | Pride | 2024-02-15

REPOSITORIES: Pride

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Similar Datasets

Uncoupling Metabolic Health from Thermogenesis via BCAA Flux in Brown Fat

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

Uncoupling Metabolic Health from Thermogenesis via BCAA Flux in Brown Fat

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

Changes in endothelial cell secretome after sirtuin-1 knock-down

Project description:Sirtuin1 (Sirt1) in skeletal muscle (SK) and fat protects against metabolic damage by stimulating insulin sensitivity. Here we report that mice with selective deletion of endothelial Sirt1 (E-Sirt1-KO) paradoxically exhibit heightened whole-body insulin sensitivity. Akt phosphorylation, glucose uptake, and glycolysis are boosted in SK and brown adipose tissue (BAT) of E-Sirt1-KO mice. E-Sirt1-KO mice have higher energy expenditure and are partially protected from high-fat diet-induced insulin resistance. Enhanced insulin sensitivity and peripheral tissue Akt phosphorylation in E-Sirt1-KO mice is transferrable to wild-type mice via the systemic circulation after surgical parabiosis. Silencing of Sirt1 in endothelial cells upregulates transcription of the F-actin-binding protein thymosin beta-4 (Tβ4), whose secretion activates Akt in skeletal myotubes. Sirt1 downregulation stimulates endothelial Tβ4 transcription through inhibition of autophagy and upregulation of nuclear factor-kappa B signaling. Thus, unlike Sirt1 in skeletal muscle and fat, endothelial Sirt1 curtails whole-body insulin sensitivity by inhibiting expression of secreted Tβ4.

2023-08-07 | PXD030565 | Pride

Apoptotic brown adipocytes enhance energy expenditure via SLC29A1-regulated extracellular inosine

Project description:Brown adipose tissue (BAT) dissipates energy and promotes cardio-metabolic health4. However, loss of BAT during obesity and aging is a principal hurdle for BAT-centered obesity therapies. So far not much is known about BAT apoptosis and signals released by apoptotic brown adipocytes. Here, untargeted metabolomics demonstrated that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched. Interestingly, this apoptotic secretome enhances expression of the thermogenic program in healthy adipocytes to maintain tissue functionality. This effect is mediated by the purine inosine which stimulates energy expenditure (EE) in brown adipocytes. Phosphoproteomic analysis demonstrated activation of the cAMP/protein kinase A signaling pathway and of pro-thermogenic transcription factors by inosine.

2022-05-31 | PXD032153 | Pride

Monocarboxylate transporters facilitate succinate uptake into brown adipocytes

Project description:Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity, and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion of it present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import. In mice, we show that both acute pharmacological inhibition of MCT1 and congenital depletion of MCT1, decrease succinate uptake into BAT and consequent catabolism. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.

2024-01-10 | PXD048056 | Pride

Regulation of cold-induced thermogenesis by the stress granule protein FAM195A

Project description:Homeothermic vertebrates are capable of surviving in cold environments by maintaining constant body temperature through thermogenesis, in which brown adipose tissue (BAT) produces heat by increasing mitochondrial oxidation along with the uncoupling of the electron transport chain and activation of uncoupling protein 1 (UCP1). Although the transcription factors that control the expression of UCP1 and genes involved in nutrient oxidation, mitochondrial function, have been extensively studied, only a few other proteins essential for BAT function have been identified. Here we describe the discovery of FAM195A, a disordered domain RNA-binding protein associated with stress granules that is required for cold-dependent thermogenesis in mice. FAM195A expression is enriched in BAT and striated muscles, and mice lacking FAM195A display whitening of BAT and an inability to survive at cold temperatures. In BAT of mice lacking FAM195A, key enzymes involved in branched chain amino acid (BCAA) metabolism, in particular leucine, and fatty acid (FA) oxidation are downregulated, impairing the physiological response to cold stress. Moreover, in vitro knock down of FAM195A impairs expression of leucine oxidation enzymes, revealing a direct role of FAM195A in the regulation of BCAA metabolism during thermogenesis

2021-06-05 | GSE164964 | GEO

Adipose subtype-selective recruitment of TLE3 in thermogenic gene programs

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

Bulk RNAseq of Mus musculus Protein Kinase D1 (Prkd1) knock-out adipose tissue in response to thermoneutral and cold exposure stress

Project description:Brown adipose tissue (BAT) has in recent times been rediscovered in adult humans, and together with work from preclinical models, shown to have the potential of providing a variety of positive metabolic benefits. These include improved insulin sensitivity and reduced susceptibility to obesity and its various co-morbidities. As such, its continued study could offer insights to therapeutically modulate this tissue to improve metabolic health. It has been reported that adipose-specific deletion of the gene for protein kinase D1 (Prkd1) enhances mitochondrial respiration and improves whole-body glucose homeostasis. We sought to determine whether these effects were mediated specifically through brown adipocytes using a Prkd1 brown adipose tissue (BAT) Ucp1-Cre-specific knockout mouse model, Prkd1BKO. We unexpectedly observed that upon both cold exposure and beta-3-AR agonist administration, Prkd1 loss in BAT did not alter canonical thermogenic gene expression or adipocyte morphology. We took an unbiased approach to assess whether other signaling pathways were altered. RNAs from cold-exposed control and Prkd1BKO were subjected to RNA-Seq analysis. These studies revealed that myogenic gene expression is altered in Prkd1BKO BAT after both acute (8 hr) and extended (4 day) cold exposure. Given that brown adipocytes and skeletal myocytes share a common precursor cell lineage expressing myogenic factor 5 (Myf5), these data suggest that loss of Prkd1 in BAT may alter the biology of preadipocytes in this depot. The data presented herein clarify the role of Prkd1 in BAT thermogenesis and present new avenues for the further study of Prkd1 function in BAT.

2023-09-01 | E-MTAB-12170 | biostudies-arrayexpress

RNA-seq and m6A-seq analysis of the control-iBAT and M14KO -iBAT, and RNA-seq analysis for the control-hBAT and M14KO-hBAT

Project description:m6A mRNA methylation in brown adipose tissue regulates systemic insulin sensitivity. We performed N6-methyladenosine (m6A) profiling and RNA seq of brown adipose tissue (BAT) from control and Mettl14-KO mice. Meanwhile, we performed RNA-seq for control and Mettl14-KO human BAT cell line as well.

2024-10-24 | GSE232491 | GEO

Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation

Project description:Brown adipose tissue (BAT) plays a pivotal role in maintaining body temperature and energy homeostasis. To identify the fuction of Ssu72 phosphatase in BAT thermogenesis, we analyzed gene expression of BAT from SSU72 WT and SSU72aKO.

2023-02-27 | GSE224337 | GEO

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