FASTING INDUCES REMODELING OF THE OREXIGENIC PROJECTIONS FROM THE ARCUATE NUCLEUS TO THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS IN A GROWTH HORMONE SECRETAGOGUE RECEPTOR-DEPENDENT MANNER

FERNÁNDEZ, GIMENA; CABRAL, AGUSTINA; TOLOSA, MARÍA JOSÉ; REY MOGGIA, ÁNGELES; DE FRANCESCO, PABLO NICOLÁS; GARCÍA ROMERO, GUADALUPE; REYNALDO, MIRTA; CALFA, GASTÓN; PERELLO, MARIO

Mar del Plata

Congreso; SAIC SAFE SAB SAP 2019; 2019

Sociedad Argentina de Investigación Clínica

Some hypothalamic circuits are known toundergo morphological and functional remodeling in order to ensure the controlof the body homeostasis. Ghrelin is a stomach-derived hormone that acts on thegrowth hormone secretagogue receptor (GHSR), and is known to play a keyregulatory role on the energy balance. Here, we hypothesized that theup-regulation of the GHSR system during fasting at the orexigenicAgouti-related peptide (AgRP)/neuropeptide Y (NPY)-producing neurons of thearcuate nucleus (ARC) would promote a morphological remodeling of the ARCprojections to the hypothalamic paraventricular nucleus (PVH) in adult mice,and that such structural changes mediate the fasting-induced activation of thePVH neurons.  We showed throughimmunostaining analysis that the total amount of the orexigenic neuropeptidesAgRP and NPY (mean intensity), the density of fibers containing theseneuropeptides (area) and the amount of AgRP and NPY per fiber (integrateddensity) were increased in the PVH of fasted mice. Similarly, analysis offluorescent signal in the PVH of NPY-GFP mice also showed that ARCnpy-->PVHprojections increase under fasting. In addition, tracing studies confirmed thatARC-->PVH projections increase under fasting. Importantly, fasting-inducedactivation of PVH neurons was impaired in ARC-ablated mice in which the densityand strength of ARCagrp/npy-->PVH projections is not increasedunder fasting. Additionally, we show that fasting-induced remodeling of theseprojections from the ARC to the PVH and the fasting-induced activation of thePVH neurons is impaired in mice with pharmacological or genetic blockage of theGHSR signaling suggesting that ghrelin signaling controls these adaptations. Toour knowledge, these are the first evidence that the connectivity betweenhypothalamic circuits controlling food intake can be remodeled in the adultbrain, depending on the energy balance conditions, and that GHSR activity is akey regulator of this phenomenon.