TH-positive pulmonary nerve fiber-epithelial interaction promotes adipose thermogenesis in male mice [C22_RNA-seq]

Cold exposure activates sympathetic neurons in adipose tissue to maintain thermal homeostasis. However, whether sympathetic activation in non-adipose tissues contributes to cross-organ regulation of adipose thermogenesis remains unclear. Here, we demonstrate the activation of TH-positive pulmonary nerve fibers (TPNFs) by cold exposure, which further promotes adipose thermogenesis. Specifically, cold exposure activates TPNFs that innervate bronchial Club cells in the lung and leads to a reduction in Secretoglobin family 3A member 1 (SCGB3A1) expression via Adrenergic Receptor β2 (ADRB2). SCGB3A1, a Club cell-specific secretory factor, binds the choline transporter SLC44A2 on adipocytes to restrict choline uptake and impair thermogenic activation. Meanwhile, TPNFs activation induces NGF secretion from Club cells, which in turn strengthens TPNFs innervation of Club cells in a feedforward loop. Importantly, the stimulation of this mechanism via tracheal infusion of the ADRB2 agonist norepinephrine (NE) enhances thermogenesis in mice.