201-LB: Overexpression of GOT1 in Brown Adipose Tissue Enhances Thermogenesis and Glucose Metabolism by Activating the Malate-Aspartate Shuttle

Abstract

Brown adipose tissue (BAT) is characterized by thermogenic and glucose-consuming properties. BAT takes up large amounts of circulating glucose during cold exposure or pharmacological stimulation of β3-adrenergic receptors (β3AR) , but glucose oxidation in mitochondria only modestly contributes as a fuel source for thermogenesis. How glucose metabolism supports thermogenesis is incompletely understood. Here, we identify a novel role of the malate-aspartate shuttle (MAS) in enhancing thermogenesis, glucose uptake and glycolysis in brown adipose tissue. We found that glutamic-oxaloacetic transaminase 1 (GOT1) , a key enzyme of the MAS, exists at very low levels in BAT but is markedly induced by cold or β3AR agonists, while other MAS enzymes (GOT2 and MDH1/2) remain unchanged. Enforced expression of Got1 in BAT increased energy expenditure in mice and further enhanced thermogenesis upon cold exposure or β3-adrenergic stimulation. Moreover, mice overexpressing Got1 in BAT exhibited enhanced glucose tolerance. Mechanistically, Got1 overexpression stimulated mitochondrial uncoupled respiration. MAS-driven thermogenesis in turn led to AMPK activation, which likely explains enhanced glucose uptake and glycolysis. Collectively, our data demonstrate a novel GOT1-MAS-AMPK axis that regulates thermogenesis and glucose metabolism in cold-activated BAT. Disclosure C. Park: None. H. Cheng: None. S. R. Lee: None. K. Eilertsen: None. J. Chang: None. Funding NIH (DK104748, 1P30GM118430, P30DK072476)