Peripheral ghrelin transmits orexigenic signals through the noradrenergic pathway from the hindbrain to the hypothalamus

Ghrelin, a gastrointestinal peptide, stimulates feeding when administered peripherally. Blockade of the vagal afferent pathway abolishes ghrelin-induced feeding, indicating that the vagal afferent pathway may be a route conveying orexigenic ghrelin signals to the brain. Here, we demonstrate that peripheral ghrelin signaling, which travels to the nucleus tractus solitarius (NTS) at least in part via the vagus nerve, increases noradrenaline (NA) in the arcuate nucleus of the hypothalamus, thereby stimulating feeding at least partially through alpha-(1) and beta-(2) noradrenergic receptors. In addition, bilateral midbrain transections rostral to the NTS, or toxin-induced loss of neurons in the hindbrain that express dopamine beta hydroxylase (an NA synthetic enzyme), abolished ghrelin-induced feeding. These findings provide new evidence that the noradrenergic system is necessary in the central control of feeding behavior by peripherally administered ghrelin.