238-LB: Cold-Dependent Regulation of GOT1 Activity in Brown Adipose Tissue and Its Effect on Thermogenesis

Abstract

The malate-aspartate shuttle (MAS) is a biochemical system that can transfer electrons from cytosolic NADH to the mitochondrial electron transport chain. The MAS regulates various biological processes in a tissue-specific manner, but its function in brown adipose tissue (BAT) thermogenesis has not been investigated. We found that glutamic-oxaloacetic transaminase 1 (GOT1), one of the key MAS enzymes, exists at very low levels in BAT but is markedly induced during cold exposure or pharmacological stimulation of β3-adrenergic receptors (β3AR) while other MAS enzymes (GOT2 and MDH1/2) remain unchanged. Our studies showed that cold-activated transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α were recruited to the Got1 promoter at the estrogen-related receptor response element (ERRE), leading to an increase in Got1 gene expression. Moreover, GOT1 protein stability was increased by reduced targeting to the proteasomal degradation. BAT-specific overexpression of Got1 in mice by using the Cre-loxP system increased energy expenditure at room temperature and improved BAT theromogeneis upon cold exposure or β3-adrenergic stimulation. Collectively, our data suggest that the β3AR-FL/NT-PGC-1α-GOT1 axis enhances BAT activity through the activation of the malate-aspartate shuttle. Disclosure C. Park: None. J. Chang: None.