Ghrelin and Glucocorticoids Independently Promote Feeding and Arcuate Nucleus Activation

Ghrelin (Ghr) is a stomach-derived hormone that exerts potent central effects, including stimulation of food intake and activation of stress mechanisms, resulting in increased circulating glucocorticoids (GC). GC can also stimulate feeding; however, whether the orexigenic effects of Ghr are mediated, at least in part, by GC remains unknown. We hypothesized that Ghr-induced GC release contributes to its orexigenic effects. Here, we used male WT mice to test if the GC receptor antagonist mifepristone (RU486) or the GC receptor agonist dexamethasone (Dex) modulate Ghr-induced food intake o Ghr-induced increment of c-Fos, a marker of neuronal activation, in the hypothalamic arcuate nucleus (ARH), a key region mediating the orexigenic actions of ghrelin. We found that RU486 did not alter the long-lasting orexigenic effect of Ghr. Also, Ghr and Dex both independently increased food intake, while their combined administration produced a further increase in feeding. Consistently, both Ghr and Dex increased the number of c-Fos cells in the ARH, and combined treatment produced an additive effect on the number of c-Fos cells. These preliminary findings indicate that Ghr and GC appear to independently engage orexigenic mechanisms, producing additive effects on food intake and neuronal activation in the ARH. This suggests that the endogenous GC response elicited by ghrelin is not a mediator of its orexigenic action but may contribute to the overall metabolic response to Ghr.