C2CD5 in noradrenergic neurons regulates thermogenesis and lipid homeostasis via norepinephrine secretion.

Thermogenesis and lipid utilization are important components of energy expenditure; they are regulated within a complex network of behavioral, hormonal, and molecular pathways that collectively maintain energy balance. Norepinephrine (NE) released by sympathetic neurons plays a critical role in modulating these processes. Here, we identify the trafficking protein C2CD5 as a key regulator of NE secretion and thermogenic function. C2CD5 is expressed in dopamine β-hydroxylase (DBH)-positive sympathetic neurons, and its expression is suppressed by obesogenic diets. Using conditional knockout mice lacking C2CD5 in DBH+ neurons, we show that loss of C2CD5 reduces NE secretion, impairs thermogenesis, lowers energy expenditure, and promotes adiposity. These effects are mitigated by NE supplementation. Our findings reveal a functional role for C2CD5 in linking sympathetic tone to systemic metabolic regulation and suggest it may represent a targetable node for metabolic disorders.