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

CABRAL A; FERNÁNDEZ, GIMENA; TOLOSA, MARÍA JOSÉ; REY-MOGGIA, ÁNGELES; CALFA, GASTÓN; DE FRANCESCO, PABLO NICOLÁS; PERELLO, MARIO

Molecular Metabolism

Elsevier

Año: 2019 vol. 32 p. 69 - 84

2212-8778

Objective:Arcuate nucleus neurons producing Agouti-related peptide (AgRP) andneuropeptide Y (NPY) (ARCAgRP/NPY neurons) are activated underenergy deficit states. ARCAgRP/NPY neurons innervate thehypothalamic paraventricular nucleus (PVH), and ARC→PVH projections arerecognized as key regulators of food intake. Plasma ghrelin levels increaseunder energy deficit states and activate ARCAgRP/NPY neurons byacting on the growth hormone secretagogue receptor (GHSR). Here, wehypothesized that activation of ARCAgRP/NPY neurons in fasted micewould promote morphological remodeling of the ARCAgRP/NPY→PVHprojections in a GHSRdependent manner. Methods: weperformed 1) fluorescent immunohistochemistry, 2) imaging of GFP signal inNPY-GFP mice and 3) DiI axonal labeling in brains of ad libitum fed or fastedmice with pharmacological or genetic blockage of the GHSR signaling, and thenestimated the density and strength of ARCAgRP/NPY→PVH fibers byassessing the mean fluorescence intensity, the absolute area with fluorescentsignal and the intensity of fluorescent signal in the fluorescent area of thePVH. Results: Wefound that: 1) the density and strength of ARCAgRP/NPY fibersincrease in the PVH of fasted mice, 2) the morphological remodeling of the ARCAgRP/NPY→PVHprojections correlates with the activation of PVH neurons, and 3) PVH neuronsare not activated in ARC-ablated mice. Also, we found that fastinginducedremodeling of ARCAgRP/NPY→PVH fibers and PVH activation is impairedin mice with pharmacological or genetic blockage of GHSR signaling. Conclusion:This evidence shows that the connectivity between hypothalamic circuits controllingfood intake can be remodeled in the adult brain, depending on the energybalance conditions, and that GHSR activity is a key regulator of thisphenomenon.