Nicotinic Acetylcholine Receptor Signaling Activates Beige Adipocytes and Mediates Systemic Metabolism

Optimal function of beige adipocytes is essential for energy balance and metabolic homeostasis. We previously identified that cholinergic receptor nicotinic α2 subunit (CHRNA2) mediates a beige fat selective signaling in mice and humans. Here, we investigate the molecular composition of CHRNA2-containing nicotinic acetylcholine receptors (nAChRs) in beige adipocytes and its impact on whole-body metabolism. Expression levels of cholinergic receptor nicotinic β2 subunit (CHRNB2) and CHRNA2 positively correlate within murine and human beige adipocytes, and both nAChRs are regulated by a spectrum of beige fat regulators. CHRNB2 is essential for the response to nAChR agonists in beige adipocytes. CHRNB2 partial agonists, a family of drugs clinically used for smoking cessation, activate both murine and human beige adipocytes. Mice deficient in Chrnb2, with both whole-body knockout or adipocyte-specific deletion, exhibit compromised adaptive thermogenesis in subcutaneous fat and more aggravated metabolic dysfunction after challenge with high-fat-diet feeding compared with control mice, underscoring the importance of the nAChR signaling in maintaining energy balance. This cholinergic signaling declines in subcutaneous fat with aging. These findings indicate CHRNB2 forms a functional receptor with CHRNA2 in beige adipocytes and highlight their potential as therapeutic targets against metabolic disorders. ARTICLE HIGHLIGHTS: Beige adipocyte activity, mediated by CHRNA2, significantly influences adipose function and systemic metabolism. The CHRNB2 subunit forms a functional receptor with CHRNA2 and is essential for the response to nicotinic acetylcholine receptor agonists in beige adipocytes. Deletion of Chrnb2 in mice compromises the adaptive response to cold in subcutaneous adipose tissue and renders exacerbated metabolic dysfunction due to diet-induced obesity. This cholinergic signaling within subcutaneous adipose tissue declines with aging. CHRNB2 partial agonists, a family of drugs clinically used for smoking cessation, activate both murine and human beige adipocytes.