β2AR Agonists Sustain Thermogenesis and Leanness via Sympathofacilitation

Abstract

Human thermogenesis depends on {beta}2-adrenoceptors ({beta}2AR) expressed in thermogenic adipocytes, which are activated by norepinephrine released from sympathetic neurons. Whether {beta}2AR also modulates thermogenesis via direct presynaptic action within sympathetic neurons has remained unclear. Here, we identify Adrb2 expression in human and rodent cervical sympathetic neurons. {beta}2AR agonism exerts neurotrophic effects and facilitates cholinergic responsiveness in mouse sympathetic neurons, indicating a sympathofacilitatory role. Selective deletion of {beta}2AR in sympathetic neurons leads to impaired nerve activity in brown adipose tissue, sympathetic neuropathy, worsened fasting-induced hypothermia, and progressive obesity in chow-fed mice--without changes in food intake. These findings uncover a presynaptic role for {beta}2AR in sustaining thermogenesis and regulating adiposity, suggesting sympathofacilitation as a therapeutic avenue for obesity. HighlightsO_LIHuman and mouse cervical sympathetic neurons express adrenoceptor beta 2 (Adrb2) C_LIO_LI{beta}2-adrenoceptor ({beta}2AR) activation is neurotrophic and facilitates sympathetic neuronal excitability C_LIO_LILoss of {beta}2AR in sympathetic neurons leads to neuropathy in brown adipose tissue and reduced sympathetic activity C_LIO_LIDeletion of {beta}2AR in sympathetic neurons exacerbates fasting-induced hypothermia and promotes obesity independently of food intake C_LI