Endothelial TrkA Coordinates Vascularization and Innervation in Thermogenic Adipose Tissue and Can Be Targeted to Control Metabolism

Abstract

Brown adipogenesis and thermogenesis in brown and beige adipose tissue (AT) involve vascular remodeling coordinated with sympathetic neuronal guidance through incompletely understood mechanisms. Here, we show that a peptide CPATAERPC, homing to the endothelium of mouse brown and beige AT, mimics nerve growth factor and identify its receptor, TrkA, as CPATAERPC cell surface target. We show that endothelial TrkA expression is selective for brown and subcutaneous AT. Analysis of mice with endothelium-specific TrkA knockout demonstrated the role of TrkA in neuro-vascular coordination supporting the thermogenic function of brown adipocytes. A hunter-killer peptide D-BAT composed of CPATAERPC and a pro-apoptotic domain ablated brown adipocytes, caused thermogenesis impairment, and predisposed mice to obesity and glucose intolerance. In a cancer model, D-BAT suppressed tumor-associated AT lipolysis and beiging. Our study reveals vascular TrkA as a potential therapeutic target.