Mast cell-driven adipocyte lipolysis promotes post-expansive VAT atrophy and ectopic hepatic steatosis

Excessive visceral fat is an essential risk factor of metabolic dysfunction-associated steatotic liver disease (MASLD). Yet, the cellular and molecular mechanisms implicated in the correlation between visceral fat metabolism and hepatic steatosis remain poorly understood. Here we report post-expansive epididymal adipose tissue (EAT) atrophy and hepatic steatosis in mice fed a high-fat diet (HFD) primarily due to elevated adipocyte lipolysis in EAT. Mast cell (MC) accumulation in EAT represents a lipolysis-associated feature. Pharmacological stabilization of MCs suppresses EAT adipocyte lipolysis, and improves EAT atrophy and hepatic steatosis. MC-derived serotonin (5-HT) correlates with visceral adipose tissue (VAT) lipolysis in HFD-fed mice as well as in MASLD patients. Conditional deletion of 5-HT from MCs or its receptor HTR2b on adipocytes demonstrates that MC-derived 5-HT promotes adipocyte lipolysis, EAT atrophy, and hepatic steatosis by binding on adipocyte HTR2b. These results suggest that MCs and MC-derived 5-HT are potential therapeutic targets for obesity-associated MASLD.