Hepatic GGPP triggers visceral adipose hypertrophy via binding with adipocyte ACSL1 in metabolic unhealthy obesity

Obesity can be classified into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO), but the molecular mechanisms remain unclear. We identify geranylgeranyl pyrophosphate (GGPP), a metabolite of the hepatic mevalonate pathway involved in cholesterol biosynthesis, as a critical mediator that distinguishes MUO from MHO. In this study, Long-term feeding of mice with starch oleate significantly upregulated the expression of geranylgeranyl diphosphate synthase (Ggpps), resulting in elevated GGPP levels. Liver-specific deletion of Ggpps reduced GGPP and selectively attenuated adipocyte hypotrophy while specifically enhancing insulin sensitivity in epididymal white adipose tissue (eWAT). Mechanistic studies suggest that GGPP modulates acyl-CoA synthetase long-chain family member 1 (ACSL1) in eWAT through non-covalent binding rather than protein geranylgeranylation, thereby inhibiting its translocation from the endoplasmic reticulum to mitochondria. The retention of ACSL1 in the ER induces eWAT-specific adipose remodeling by promoting triglyceride (TG) synthesis and suppressing lipid oxidation. These findings establish a “liver-adipose” axis mediated by the hepatic metabolite GGPP via its non-covalent interaction with adipocyte ACSL1, highlighting potential therapeutic targets for metabolic dysfunction associated with metabolically unhealthy obesity.