The hypothalamic action of ghrelin is required for a full response of the hypothalamic?pituitary?adrenal (HPA) axis to fasting

GIMENA FERNANDEZ; LAURA HINTE; ANDRES GIOVAMBATTISTA; AGUSTINA CABRAL; MARÍA JOSE TOLOSA; GUADALUPE GARCÍA-ROMERO; GUILLERMINA ZUBIRÍA; MIRTA REYNALDO; MARIO PERELLO

Congreso; Segunda Reunión Conjunta de Sociedades de BioCiencias; 2017

SAIC

Ghrelin is a stomach-derived hormone that regulates food intake and neuroendocrine axis via its action on the GHSR (growth hormone secretagogue receptor). The administration of ghrelin actives corticotropin-releasing factor (CRF) neurons of the hypothalamic paraventricular nucleus (PVN) and, as a consequence, the HPA axis via inhibition of the local GABA tone and independently of the neuropeptide Y (NPY)/GABA neurons of the arcuate nucleus (ARC). Under fasting ghrelin levels increase; however, the impact of endogenous increments of plasma ghrelin on the HPA axis is currently unknown. Here we studied the response of the HPA axis to fasting of wild-type (wt) mice, GHSR-deficient mice and mice expressing GHSR only in GABA neurons. In addition, we quantified if fasting affects the NPY and GABA inputs to the PVN in an in vitro setting and in mice expressing tdTomato fluorescent protein in GABA neurons. Results: As compared to wt mice, GHSR-deficient mice showed an impaired fasting-induced increase of both plasma corticosterone and the marker of neuronal activation, c-Fos, in the PVN (corticosterone: 204±30 vs. 113±30 ng/ml; c-Fos: 44±9 vs. 13±6 cells/side, respectively; p≤0.05, 2-way ANOVA). In contrast, mice expressing GHSR only in GABA neurons displayed a full response to fasting. As compared to ad libitum fed mice, fasted mice showed an increase of the NPY-fiber density and an increase of the area of tdTomato positive fibers in the PVN (NPY-fibers: 0.09±0.02 vs. 0.17±0.02 OD; td-Tomato:28.0±3.1 vs. 38.1±1.5 % of total area; respectively; p≤0.05, T-test). As compared to PVN explants of ad libitum fed mice, PVN explants of fasted mice showed a reduction of basal and KCl-stimulated GABA release (basal:4.5±0.3 and 3.1±0.5; KCl:6.1±0.3 and 4.3±0.8 % of total incorporated tracer, respectively; p≤ 0.05, two-way ANOVA). Thus, these data indicate that ghrelin signaling in GABA neurons is relevant for the normal response of the HPA axis to fasting.