The full expression of fasting-induced torpor requires beta 3-adrenergic receptor signaling.

Torpor, a controlled rapid drop in metabolic rate and body temperature (Tb), is a hypometabolic adaptation to stressful environmental conditions, which occurs in many small mammals, marsupials, and birds. To date, signaling pathways required for torpor have not been identified. We examined the role of the sympathetic nervous system (SNS) in mediating the torpor adaptation to fasting by telemetrically monitoring the Tb of dopamine beta-hydroxylase knock-out (Dbh-/-) mice, which lack the ability to produce the SNS transmitters, norepinephrine (NE), and epinephrine. Control (Dbh+/-) mice readily reduced serum leptin levels and entered torpor after a fast in a cool environment. In contrast, Dbh-/- mice failed to reduce serum leptin and enter torpor under fasting conditions, whereas restoration of peripheral but not central NE lowered serum leptin levels and rescued the torpor response. Torpor was expressed in fasted Dbh-/- mice immediately after administration of either the nonselective beta-adrenergic receptor agonist isoproterenol or the beta3-adrenergic receptor (AR)-specific agonist CL 316243 [disodium (RR)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxazole-2,2-dicarboxylate], but not after administration of beta1, beta2, or alpha1 agonists. Importantly, the beta3-specific antagonist SR 59230A [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate] severely blunted fasting-induced torpor in control mice, whereas other AR antagonists were ineffective. These results define a critical role of peripheral SNS activity at beta3-AR-containing tissues in the torpor adaptation to limited energy availability and cool ambient temperature.