β2AR Agonists Sustain Thermogenesis and Leanness via Sympathofacilitation

Cheung, S. W.; Sidarta-Oliveira, D.; Yao, L.; Zhu, Y.; Sarker, G.; Lundh, S.; Morgan, D. A.; Qu, J.; Wilcox, S.; Vyazovskiy, V.; Paterson, D. J.; Li, D.; Rahmouni, K.; Domingos, A.

doi:10.1101/2025.06.13.659468

bioRxiv · 10.1101/2025.06.13.659468

β2AR Agonists Sustain Thermogenesis and Leanness via Sympathofacilitation

Cheung, S. W.·Sidarta-Oliveira, D.·Yao, L.·Zhu, Y.·Sarker, G.·Lundh, S.·Morgan, D. A.·Qu, J.·Wilcox, S.·Vyazovskiy, V.·Paterson, D. J.·Li, D.·Rahmouni, K.·Domingos, A.

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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

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Cheung, S. W., Sidarta-Oliveira, D., Yao, L., Zhu, Y., Sarker, G., Lundh, S., Morgan, D. A., Qu, J., Wilcox, S., Vyazovskiy, V., Paterson, D. J., Li, D., Rahmouni, K., Domingos, A.. 2025-06-17. β2AR Agonists Sustain Thermogenesis and Leanness via Sympathofacilitation. https://doi.org/10.1101/2025.06.13.659468

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