Ghrelin activates hypophysiotropic CRF neurons through NPYindependent neuronal circuitries.

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

Congreso; XXVII congreso de la SAN; 2012

Ghrelin is a stomach-derived hormone that regulates appetite and neuroendocrine functions. We have shown that ghrelin activates hypophysiotropic corticotropin-releasing factor (CRF)-producing neurons of the paraventricular nucleus (PVN) and the hypothalamic-pituitary-adrenal (HPA) axis via an indirect mechanism. Since ghrelin activates the neuropeptide Y (NPY) neurons of the arcuate nucleus (ARC), which in turn activates CRF neurons, we tested if intact ARC or NPY signaling are required for ghrelininduced activation of hypophysiotropic CRF neurons. For this, we administrated ghrelin [2 μg, intra-cerebro-ventricularly (ICV)] to mice with either lesion of the ARC by neonatal treatment with monosodium glutamate (MSG) or previously treated with a combination of specific NPY-1 and NPY-5 receptor antagonists (BIBO3304 and CGP71683 1 μg each, ICV). In MSG mice, we found that ghrelin fully activates c-fos -a marker of cellular activation- in the CRF neurons of the PVN despite the significant reduction of NPY neurons and fibers they have in the ARC and PVN, respectively. In mice with pharmacological blockage of NPY signaling, we found that hypophysiotropic CRF neurons also fully responded to ghrelin. In addition, we found that ghrelin administration directly into the PVN (0.2 μg) also activates both the CRF neurons of the PVN and the HPA axis. Thus, we conclude that ghrelin activates hypophysiotropic CRF neurons through a local neuro-circuitry that is independent of NPY signaling.