Fasting‐induced torpor requires β3 adrenergic receptor signaling

Abstract

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 β-hydroxylase knockout (Dbh) −/− mice which lack the ability to produce the SNS transmitters, norepinephrine (NE) and epinephrine (Epi). 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 non-selective β adrenergic receptor agonist, isoproterenol, or the β3 AR specific agonist, CL316243, but not after administration of β1, β2, or α1 agonists. Importantly, a β3-specific antagonist 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 β3 AR-containing tissues in the torpor adaptation.