An immune-beige adipocyte communication via nicotinic acetylcholine receptor signaling

Beige adipocytes have been recently shown to regulate energy dissipation when activated, and help organisms defend against hypothermia and obesity. Prior reports indicate beige-like adipocytes exist in adult humans and may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated beige adipocytes, we uncovered that the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) is induced in subcutaneous fat during the activation of these cells, and that acetylcholine-producing immune cells within this tissue regulate this signaling pathway via paracrine mechanisms. CHRNA2 functions selectively in uncoupling protein 1 (Ucp1)(+) beige adipocytes, increasing thermogenesis through a cAMP and PKA pathway. Furthermore, this signaling via CHRNA2 is conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromises the cold-induced thermogenic response selectively in subcutaneous fat and exacerbates high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of beige fat regulation in vivo leads to detrimental consequences. Our results reveal a beige-selective immune-adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors (nAChRs) in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity.