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Abstract

A strong association between leucine and obesity has been well established; however, the role of leucine catabolic enzymes in adipose tissue remains largely unknown. Here, we show that knockdown of the leucine catabolic enzyme AU RNA-binding methylglutaconyl-CoA hydratase (AUH) in brown adipocytes reduces thermogenesis, while AUH over-expression has the opposite effect both in vivo and in vitro. Mechanistically, AUH partially promotes uncoupling protein 1 (UCP1) expression through its metabolite 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). HMG-CoA directly HMGylates peroxisome proliferator-activated receptor gamma (PPARγ) on lysine 386, enhancing its transcriptional activity to increase UCP1 expression. In addition, AUH binds to and stabilizes Ucp1 mRNA via its RNA-binding function. Moreover, we discovered that AUH promotes white adipose tissue browning; AUH expression in human white adipose tissue is inversely correlated with adiposity, and over-expression of AUH in adipose tissue protects male mice against high-fat diet-induced obesity. Collectively, these results provide new insights into the crosstalk between amino acid metabolism and thermogenesis and identify a novel post-translational modification of PPARγ. The authors show that the leucine metabolic enzyme AUH promotes fat burn and protects against obesity. AUH drives thermogenesis via Ucp1 mRNA stabilization and PPARγ modification via metabolite HMG-CoA, linking amino acid metabolism to weight regulation.