Divergent neuronal circuitries underlying acute orexigenic effects of peripheral or central ghrelin: critical role of brain accessibility

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

JOURNAL OF NEUROENDOCRINOLOGY.

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2014 p. 1 - 14

0953-8194

Ghrelin is an octanoylated peptide hormone that potently and rapidly increases food intake. The orexigenic action of ghrelin involves the hypothalamic arcuate nucleus (ARC), which is accessible to plasma ghrelin and expresses high levels of the ghrelin receptor. Local administration of ghrelin in a variety of other brain nuclei also increases food intake. It is currently unclear, however, if these non-ARC ghrelin brain targets are impacted by physiological increases of plasma ghrelin. Thus, the current study was designed to clarify which ghrelin brain targets participate in the short-term orexigenic actions of ghrelin. First, c-Fos induction into mouse brains centrally or peripherally treated with ghrelin was analyzed. It was confirmed that peripherally administered ghrelin dose dependently increases food intake and mainly activates c-Fos in ARC neurons. In contrast, centrally administered ghrelin activates c-Fos in a larger number of brain nuclei. To determine which nuclei are directly accessible to ghrelin, mice were centrally or peripherally injected with a fluorescent ghrelin tracer. It was found that peripherally injected tracer mainly accesses the ARC while centrally injected tracer reaches most brain areas known to express ghrelin receptors. Following that, ghrelin effects in ARC-ablated mice were tested and it was found that these mice failed to increase food intake in response to peripherally administered ghrelin but fully responded to centrally administered ghrelin. ARC-ablated mice showed similar patterns of ghrelin-induced c-Fos expression as seen in control mice with the exception of the ARC, where no c-Fos was found. Thus, peripheral ghrelin mainly accesses the ARC, which is required for the orexigenic effects of the hormone. Central ghrelin accesses a variety of nuclei, which can mediate the orexigenic effects of the hormone even in the absence of an intact ARC.