Pulmonary cold sensing through Club cells triggers adipose thermogenesis to ameliorate obesity

Cold exposure is a well-known trigger for thermogenesis, primarily through skin cold-sensitive neurons activating adipose metabolism via the central nervous system (CNS). However, whether the lungs-also exposed to cold air-function as a cold sensor and regulate metabolism remains unknown. Here, using CC10-Cre- and adeno-associated virus (AAV)-based mouse models, we uncover a pulmonary cold sensing system that drives thermogenesis, establishing a peripheral thermoregulatory mechanism. Specifically, we identify KCNK2 channels in Club cells within the bronchial epithelium as primary pulmonary cold sensors, where cold exposure enhances Irisin expression and secretion via Ca²⁺ fluctuations to drive thermogenesis in adipose tissue. Notably, pharmacological activation of this pathway via fluoxetine tracheal infusion enhances thermogenesis and ameliorates obesity in mice, highlighting a potential anti-obesity delivery strategy.