Functional Inactivation of Mast Cells Enhances Subcutaneous Adipose Tissue Browning in Mice

Adipose tissue browning and systemic energy expenditure provide a defense mechanism against obesity and associated metabolic diseases. In high-cholesterol Western diet-fed mice, mast cell (MC) inactivation ameliorates obesity and insulin resistance and improves the metabolic rate, but a direct role of adipose tissue MCs in thermogenesis and browning remains unproven. Here, we report that adrenoceptor agonist norepinephrine-stimulated metabolic rate and subcutaneous adipose tissue (SAT) browning are enhanced in MC-deficient Kit^w-sh/w-sh mice and MC-stabilized wild-type mice on a chow diet. MC reconstitution to SAT in Kit^w-sh/w-sh mice blocks these changes. Mechanistic studies demonstrate that MC inactivation elevates SAT platelet-derived growth factor receptor A (PDGFRα⁺) adipocyte precursor proliferation and accelerates beige adipocyte differentiation. Using the tryptophan hydroxylase 1 (TPH1) inhibitor and TPH1-deficient MCs, we show that MC-derived serotonin inhibits SAT browning and systemic energy expenditure. Functional inactivation of MCs or inhibition of MC serotonin synthesis in SAT promotes adipocyte browning and systemic energy metabolism in mice.