Fasting induces remodeling of the orexigenic projections from the arcuate nucleus to the hypothalamic paraventricular nucleus, in a growth hormone secretagogue receptor–dependent manner

OBJECTIVE: Arcuate nucleus (ARC) neurons producing Agouti-related peptide (AgRP) and neuropeptide Y (NPY; ARC(AgRP/NPY) neurons) are activated under energy-deficit states. ARC(AgRP/NPY) neurons innervate the hypothalamic paraventricular nucleus (PVH), and ARC→PVH projections are recognized as key regulators of food intake. Plasma ghrelin levels increase under energy-deficit states and activate ARC(AgRP/NPY) neurons by acting on the growth hormone secretagogue receptor (GHSR). Here, we hypothesized that activation of ARC(AgRP/NPY) neurons in fasted mice would promote morphological remodeling of the ARC(AgRP/NPY)→PVH projections in a GHSR-dependent manner. METHODS: We performed 1) fluorescent immunohistochemistry, 2) imaging of green fluorescent protein (GFP) signal in NPY-GFP mice, and 3) DiI axonal labeling in brains of ad libitum fed or fasted mice with pharmacological or genetic blockage of the GHSR signaling and then estimated the density and strength of ARC(AgRP/NPY)→PVH fibers by assessing the mean fluorescence intensity, the absolute area with fluorescent signal, and the intensity of the fluorescent signal in the fluorescent area of the PVH. RESULTS: We found that 1) the density and strength of ARC(AgRP/NPY) fibers increase in the PVH of fasted mice, 2) the morphological remodeling of the ARC(AgRP/NPY)→PVH projections correlates with the activation of PVH neurons, and 3) PVH neurons are not activated in ARC-ablated mice. We also found that fasting-induced remodeling of ARC(AgRP/NPY)→PVH fibers and PVH activation are impaired in mice with pharmacological or genetic blockage of GHSR signaling. CONCLUSION: This evidence shows that the connectivity between hypothalamic circuits controlling food intake can be remodeled in the adult brain, depending on the energy balance conditions, and that GHSR activity is a key regulator of this phenomenon.