Ep300-mediated acetylation plasticity in the acetyl-CoA metabolic network drives the protective role of intensive lifestyle intervention in visceral white adipose tissue

Obesity is a major global health concern and a key driver of metabolic disorders. Intensive lifestyle intervention (ILI), combining caloric restriction and exercise, effectively promotes weight loss and improves metabolic health. Visceral white adipose tissue (vWAT) displays remarkable metabolic plasticity during weight fluctuation, yet the molecular mechanisms underlying ILI-induced remodeling remain unclear. We developed a mouse model to simulate weight fluctuations induced by high-fat diet (HFD) followed by weight loss through ILI. Multi-omics data (proteomics, acetylomics, transcriptomics, and ChIP-seq) were collected from vWAT to investigate acetylation changes and metabolic reprogramming. Adeno-associated virus (AAV) and lentivirus vectors were employed to suppress Ep300 expression in vWAT, followed by an analysis of the effects on lipid accumulation, body weight, and overall metabolic health. Ep300 expression was elevated under HFD and decreased after ILI, paralleling global changes in acetylation. Multi-omics integration revealed that acetyl-CoA metabolic network, encompassing glycolysis, the tricarboxylic acid (TCA) cycle, and fatty acid metabolism, was identified as a central hub regulated by Ep300. H3K36ac emerged as a key histone acetylation mark associated with nutritional states and Ep300 activity. Ep300 knockdown through AAV and lentivirus reproduced several metabolic benefits of ILI, including reduced lipid accumulation and body weight. Depot-specific responses were observed. Multi-omics integration in vWAT after Ep300 knockdown suggested that Ep300-mediated acetylation network in adipose tissue exerts an effect similar to ILI in reducing lipid accumulation, while positioning mitochondria as a crucial functional compartment within this regulatory network. These findings suggest that Ep300-mediated acetylation plasticity contributes to the adaptive remodeling of vWAT during weight loss. By linking acetyl-CoA metabolism with mitochondrial function, Ep300 may serve as an epigenetic regulator coordinating metabolic flexibility during lifestyle intervention. These findings provide mechanistic insight into how lifestyle intervention reprograms adipose tissue and highlight the epigenetic flexibility underlying metabolic recovery after obesity.