Divergent neuronal circuitries underlying orexigenic effects of circulating or cerebrospinal fluid ghrelin: critical role of brain accessibility

AGUSTINA CABRAL; GIMENA FERNANDEZ; ANABELA PATRONE; SPRING VALDIVIA; MIRTA REYNALDO; MARIO PERELLO

Congreso; XXVIII congreso de la SAN; 2013

Ghrelin is a hormone that stimulate food intake via activation of growth hormone secretagogue receptor (GHSR). This study was aimed to delineate the neuronal circuits that mediate the orexigenic effect of ghrelin. First, we analyzed the c-Fos induction in the brain of mice centrally or systemically treated with ghrelin. We found that peripherally administrated ghrelin dose-dependently increased food intake and number of c-fos positive cells in the hypothalamic arcuate nucleus (ARC) and solitary tract nucleus. In contrast, centrally administrated ghrelin increased food intake and number of c-fos positive cells in most nuclei expressing GHSR. To determine which nuclei are directly affected by ghrelin, we centrally or systemically injected mice with fluorescein-ghrelin (F-ghrelin). We found that peripherally injected F-ghrelin only accessed to the ARC while centrally injected F-ghrelin reached most GHSR-expressing brain areas. Then, we tested ghrelin effects in ARC ablated mice. These mice failed to respond to peripheral ghrelin but fully responded to centrally administrated ghrelin. ARC-ablated mice showed similar ghrelin-induced c-fos expression as seen in control mice, but in the ARC, where no c-Fos was found. Thus, circulating ghrelin mainly accesses to the ARC, which is required for orexigenic effects of the hormone. Cerebrospinal ghrelin accesses to a variety of nuclei, which can mediate the orexigenic effects of the hormone even in the absence of the ARC.