BCAA catabolism drives adipogenesis via an intermediate metabolite and promotes subcutaneous adipose tissue expansion during obesity

Branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) have emerged as major players in metabolic health and diseases, but the underlying mechanisms remain obscure. Here, we report that BCAA catabolism drives adipogenesis via an intermediate metabolite of leucine and promotes subcutaneous white adipose tissue (sWAT) expansion during obesity. Genetic analyses of humans and mice reveal that the BCAA catabolic pathway in WAT is strongly correlated with adipose physiology and obesity traits. Altering BCAA catabolism in mature adipocytes exerts minor effects on adiposity in mice. However, enhancing adipose BCAA catabolism via FABP4-Cre-mediated Bckdk deletion promotes diet-induced obesity while blocking adipose BCAA catabolism through Bckdha ablation does the opposite. Intriguingly, the catabolism of BCAAs elicits fat depot-specific responses and promotes sWAT extension and adipogenesis in a cell-autonomous manner. Mechanistically, BCAA catabolism drives adipocyte differentiation via an intermediate metabolite of leucine, which activates mTORC1 and polyamine synthesis from methionine to promote the expression of adipogenic master regulators. Together, these results demonstrate that BCAA catabolism promotes adipogenesis and sWAT expansion during obesity. The crosstalk between leucine and methionine metabolism driven by the catabolic intermediate highlights an unexpected regulatory role of amino acids in metabolic health and diseases.