Ghrelin signaling mediates fasting-induced activation of the hypophysiotropic CRF neurons via recruitment of the NPY/AGRP/GABA neurons

AGUSTINA CABRAL; GIMENA FERNANDEZ; M FLORENCIA ANDREOLI; MIRTA REYNALDO ; MARÍA DE LOS ÁNGELES REY MOGGIA; GUADALUPE GARCÍA ROMERO; MARÍA JOSÉ TOLOSA; GUILLERMINA ZUBIRÍA; MARIO PERELLÓ

Mar del Plata

Congreso; Reunion conjunta SAIC SAI SAFIS 2018; 2018

Ghrelin is a stomach-derived hormone that acts on the growth hormone secretagogue receptor (GHSR).Plasma ghrelin increases under fasting, when it promotes appetite and activation of the hypothalamic?pituitary?adrenal (HPA) via its action on corticotropin-releasing factor (CRF) neurons of the paraventricularnucleus (PVN). The neuronal circuits by which ghrelin regulates these actions are unclear. Here, we tested inmale mice with pharmacological or genetic blockage of GHSR the effect of 48 h fasting on the PVN CRFneurons and on the neuropeptide Y (NPY)/agouti-related protein (AgRP)/GABA neurons of the arcuatenucleus (ARC), which sense plasma factors and regulate the PVN. Results: As compared to fed mice, fastedmice had an increase of the number of PVN CRF cells (3.57±0.22 fold increase, p≤0.05, T-test) and of theNPY/AgRP-fiber intensity (NPY-fibers: 0.09±0.02 vs 0.17±0.02 OD; AgRP-fibers:3428±754 vs 10783±1490intensity; GFP-fibers: 8558±965 vs 16799±1771 intensity in mice expressing GFP in NPY neurons, p≤0.05, Ttest).As compared to wild-type (WT) mice, GHSR-deficient mice had lower levels of plasma corticosteroneand 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, p≤0.05, 2-way ANOVA). Similarly, fasted mice with pharmacological blockage ofGHSR showed lower c-Fos and of NPY-fiber intensity in the PVN (c-Fos: 119±19 vs 177±13 cells/side; NPYfiber:0.21±0.01 vs 0.45±0.04 OD, p≤0.05, T-test). Fasted mice expressing tdTomato fluorescent protein inGABA neurons had more tdTomato fibers in PVN (1.36±0.08 fold increase, p≤0.05 vs fed mice, T-test). Ascompared to fed mice, PVN explants of fasted mice had a reduction of the basal and KCl-stimulated GABArelease (basal: 4.5±0.3 vs 3.1±0.5 and KCl: 6.1±0.3 vs 4.3±0.8 % of total incorporated tracer, p≤ 0.05, 2-wayANOVA). Current results indicate that ghrelin signaling mediates fasting-induced activation of thehypophysiotropic CRF neurons via recruitment of the NPY/AGRP/GABA neurons.