Β 2 AR Agonists Sustain Thermogenesis and Leanness via Sympathofacilitation.

UNLABELLED: Human thermogenesis depends on β2-adrenoceptors (β2AR) expressed in thermogenic adipocytes, which are activated by norepinephrine released from sympathetic neurons. Whether β2AR 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. β2AR agonism exerts neurotrophic effects and facilitates cholinergic responsiveness in mouse sympathetic neurons, indicating a sympathofacilitatory role. Selective deletion of β2AR 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 β2AR in sustaining thermogenesis and regulating adiposity, suggesting sympathofacilitation as a therapeutic avenue for obesity.

HIGHLIGHTS: Human and mouse cervical sympathetic neurons express adrenoceptor beta 2 ( Adrb2 ) β2-adrenoceptor (β2AR) activation is neurotrophic and facilitates sympathetic neuronal excitabilityLoss of β2AR in sympathetic neurons leads to neuropathy in brown adipose tissue and reduced sympathetic activityDeletion of β2AR in sympathetic neurons exacerbates fasting-induced hypothermia and promotes obesity independently of food intake.