Adipose GGPPS stabilizes BCAT2 to orchestrate BCAA catabolism and lipid mobilization in fasting-induced liver remodeling.

Organisms adapt to fasting by remodeling energy metabolism across tissues. We identify geranylgeranyl pyrophosphate synthase (GGPPS) in white adipose tissue (WAT) as a fasting-responsive regulator that orchestrates lipolysis and branched-chain amino acid (BCAA) metabolism. In mice, fasting downregulates GGPPS, destabilizing the BCAA-catabolizing enzyme BCAT2 via enhanced ubiquitination. Mechanistically, GGPPS scaffolds the deubiquitinase OTUB1 and BCAT2 to stabilize BCAT2, promoting BCAA catabolism. Elevated BCAAs activate adipocyte lipolysis and enhance hepatic fatty acid oxidation. Adipose-specific deletion of Ggpps phenocopies fasting responses, including enhanced lipolysis and systemic BCAA elevation. Conversely, BCAA supplementation promotes adipose lipolysis, protects against diet-induced obesity, and facilitates hepatic oxidative adaptation. In fasting mice, BCAA supplementation enhanced weight loss efficiency and prevented aberrant hepatic lipid accumulation. These findings identify GGPPS as a potential central node linking amino acid and lipid metabolism during early fasting within a multi-organ metabolic circuit.