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Significance Physiologic systems often maintain homeostasis through negative-feedback loops. Unlike most regulatory targets for the sympathetic nervous system, interscapular brown adipose tissue (BAT) lacks parasympathetic inputs that might otherwise counterbalance the stimulatory effects of catecholamines. We found that the cAMP response element-binding protein (CREB) coactivator cAMP-regulated transcriptional coactivator 3 (CRTC3) reduces BAT function by down-regulating sympathetic nerve activity and vascularization. Mice with a knockout of CRTC3 in BAT have reduced adiposity and are more cold tolerant. CRTC3 inhibits BAT activity by disrupting the expression of neurotrophins and proangiogenic factors that otherwise promote sympathetic innervation and vascularization of BAT. These studies highlight an important feedback mechanism that maintains energy homeostasis via its effects in brown fat.

cAMP-inducible coactivator CRTC3 attenuates brown adipose tissue thermogenesis