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Adipose GGPPS Stabilizes BCAT2 to Orchestrate BCAA Catabolism and Lipid Mobilization in Fasting-Induced Liver Remodeling

ABSTRACT: Organisms adapt to fasting by remodeling energy metabolism across tissues, with white adipose tissue (WAT) serving as a key energy reservoir. However, the molecular cues that initiate lipid mobilization during early fasting remain incompletely defined. Here, we identify geranylgeranyl pyrophosphate synthase (GGPPS) as a fasting-responsive regulator that orchestrates lipolysis and branched-chain amino acid (BCAA) metabolism. In mice, 24 hours of fasting marks a metabolic inflection point characterized by hepatic triglyceride accumulation, WAT mass reduction, and a sharp elevation in circulating BCAAs. Proteomic profiling revealed that fasting downregulates GGPPS in both inguinal and epididymal WAT, which in turn destabilizes BCAT2-a key BCAA-catabolizing enzyme-via enhanced K63-linked ubiquitination. Mechanistically, GGPPS scaffolds the deubiquitinase OTUB1 and BCAT2 to stabilize BCAT2 protein level, thereby promoting BCAA catabolism. Elevated BCAAs activate lipolysis in adipocytes and enhance hepatic fatty acid oxidation. Adipose-specific deletion of Ggpps in mice phenocopies fasting responses, including enhanced lipolysis, hepatic lipid accumulation, and systemic BCAA elevation. Conversely, BCAA supplementation promotes adipose lipolysis, protects against diet-induced obesity, and facilitates hepatic oxidative adaptation. Importantly, we found that BCAA supplementation during fasting not only enhanced weight loss efficiency, but also prevented aberrant hepatic lipid accumulation typically induced by prolonged fasting in mice. These findings uncover GGPPS as a central node linking amino acid and lipid metabolism during early fasting and establish a multi-organ metabolic circuit that coordinates the transition from carbohydrate to lipid-based energy utilization.

ORGANISM(S): Mus Musculus

SUBMITTER: Lei Fang

PROVIDER: PXD068547 | iProX | Thu Sep 18 00:00:00 BST 2025

REPOSITORIES: iProX

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Adipose GGPPS Stabilizes BCAT2 to Orchestrate BCAA Catabolism and Lipid Mobilization in Fasting-Induced Liver Remodeling

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