263-LB: Functional Inactivation of Mast Cell Enhances Subcutaneous Adipose Tissue Browning through Decreasing Serotonin Release in Mice

Abstract

Introduction: Therapeutic targeting of brown adipocyte-mediated thermogenesis to increase energy expenditure may offer a viable alternative approach to combat obesity and metabolic disease. Several immune signaling regulated beige fat thermogenic circuits were established in adipose tissues. Genetic deficiency and pharmacological stabilization of Mast Cells (MCs) increased metabolic rate and UCP1 expression in BAT in western diet-fed mice in concert with their obesity and insulin resistance improvement. Serotonin is an important regulator of energy balance. Yet, it remains unknown whether MCs play a direct role in energy homeostasis or the above-mentioned changes in energy expenditure are merely a consequence of mouse body weight reduction. Methods and Results: We compared metabolic rate differences between WT and MC-deficient Kitw-sh/w-sh mice. In the context of mice on a chew diet, norepinephrine (NE)-stimulated metabolic rate is increased in MC-deficient Kitw-sh/w-sh mice and MC-stabilized wide-type (WT) mice. Histological staining, qPCR and western blot showed UCP1 and other thermogenic genes also increased in these mice. Such functional inactivation of MCs enhances thermogenesis and browning in subcutaneous adipose tissues (SAT), but not in brown (BAT) and epididymal adipose tissues (EAT). MC reconstitution to SAT blocks the aforesaid changes in Kitw-sh/w-sh mice. Mechanistic studies demonstrate that functional inactivation of MCs not only elevates the numbers and proliferation of PDGFRα+ bipotential adipocyte precursors but also accelerates beige adipocyte differentiation in SAT. Using tryptophan hydroxylase 1 inhibitor and Tph1-/- mast cells, we show that MC-derived serotonin inhibits SAT beige adipocyte biogenesis and systemic energy expenditure. Conclusions: Together, functional inactivation of MCs or inhibition of MC serotonin synthesis in SAT promotes adipocyte browning and systemic energy metabolism in mice. Disclosure X. Zhang: None. Funding American Heart Association