Adrenergic modulation of melanocortin pathway by hunger signals

Norepinephrine (NE) is a well-known appetite regulator, and the nor/adrenergic system is targeted by several anti-obesity drugs. To better understand the circuitry underlying adrenergic appetite control, here we investigated the paraventricular hypothalamic nucleus (PVN), a key brain region that integrates energy signals and receives dense nor/adrenergic input, using a mouse model. We found that PVN NE level increases with signals of energy deficit and decreases with food access. This pattern is recapitulated by the innervating catecholaminergic axon terminals originating from NTS(TH)-neurons. Optogenetic activation of rostral-NTS(TH) → PVN projection elicited strong motivation to eat comparable to overnight fasting whereas its inhibition attenuated both fasting-induced & hypoglycemic feeding. We found that NTS(TH)-axons functionally targeted PVN(MC4R)-neurons by predominantly inhibiting them, in part, through α1-AR mediated potentiation of GABA release from ARC(AgRP) presynaptic terminals. Furthermore, glucoprivation suppressed PVN(MC4R) activity, which was required for hypoglycemic feeding response. These results define an ascending nor/adrenergic circuit, NTS(TH) → PVN(MC4R), that conveys peripheral hunger signals to melanocortin pathway.