Ghrelin counteracts insulin-induced activation of vagal afferent neurons via growth hormone secretagogue receptor

• Ghrelin inhibits insulin-induced [Ca2 +]i increase in nodose ganglion (NG) neurons.
• Ghrelin interacts with GHSR to counteract insulin in NG neurons.
• Ghrelin counteracts insulin but not CCK in increasing [Ca2 +]i in NG neurons.
• This interaction may inform brain of ghrelin- vs. insulin-dominant metabolic states.

Vagal afferent nerves sense meal-related gastrointestinal and pancreatic hormones and convey their information to the brain, thereby regulating brain functions including feeding. We have recently demonstrated that postprandial insulin directly acts on the vagal afferent neurons. Plasma concentrations of orexigenic ghrelin and anorexigenic insulin show reciprocal dynamics before and after meals. The present study examined interactive effects of ghrelin and insulin on vagal afferent nerves. Cytosolic Ca2 + concentration ([Ca2 +]i) in isolated nodose ganglion (NG) neurons was measured to monitor their activity. Insulin at 10− 7 M increased [Ca2 +]i in NG neurons, and the insulin-induced [Ca2 +]i increase was inhibited by treatment with ghrelin at 10− 8 M. This inhibitory effect of ghrelin was attenuated by [D-Lys3]-GHRP-6, an antagonist of growth hormone-secretagogue receptor (GHSR). Des-acyl ghrelin had little effect on insulin-induced [Ca2 +]i increases in NG neurons. Ghrelin did not affect [Ca2 +]i increases in response to cholecystokinin (CCK), a hormone that inhibits feeding via vagal afferent neurons, indicating that ghrelin selectively counteracts the insulin action. These results demonstrate that ghrelin via GHSR suppresses insulin-induced activation of NG neurons. The action of ghrelin to counteract insulin effects on NG might serve to efficiently inform the brain of the systemic change between fasting-associated ghrelin-dominant and fed-associated insulin-dominant states for the homeostatic central regulation of feeding and metabolism.