FASTING INDUCES REMODELING OF HYPOTHALAMIC NEURONAL CIRCUITS CONTROLLING FOOD INTAKE AND NEUROENDOCRINE AXIS IN A GROWTH HORMONE SECRETAGOGUE RECEPTOR-DEPENDENT MANNER

FERNANDEZ, GIMENA

Congreso; XXXV Reunion Anual SAN2020; 2020

The morphological and functional remodeling of neuronal circuits have been proposed to play a key role to ensure the control of the body homeostasis1. Under energy-deficit states, the arcuate nucleus (ARC) neurons producing Agouti-related peptide (AgRP) and neuropeptide Y (NPY; ARCAgRP/NPY neurons) are activated and help to coordinate neuroendocrine and behavioral responses, including food intake, through projections to the hypothalamic paraventricular nucleus (PVH; ARC→PVH projections)2. Plasma ghrelin levels increase under energy-deficit states and activate ARCAgRP/NPY neurons by acting on the growth hormone secretagogue receptor (GHSR)3. Here, we hypothesized that activation of ARCAgRP/NPY neurons in fasted mice would promote morphological remodeling of the ARCAgRP/NPY→PVH projections in a GHSR-dependent manner, and such structural changes mediate the fasting-induced activation of the hypophysiotropic corticotrophin-releasing factor (CRF) producing neurons of the PVH. Using different experimental strategies we found that: the density and strength of ARCAgRP/NPY fibers increase in the PVH of fasted mice; the morphological remodeling of the ARCAgRP/NPY→PVH projections correlates with the activation of the hypophysiotropic CRF neuron; and the PVH neurons are not activated in ARC-ablated mice. We also found that the remodeling of ARCAgRP/NPY→PVH fibers and PVH activation are impaired in mice with pharmacological or genetic blockage of GHSR signaling. This evidence shows that the connectivity between hypothalamic circuits controlling food intake and neuroendocrine responses can be remodeled in the adult brain, depending on the energy balance conditions, and that GHSR activity is a key regulator of this phenomenon.[1] Garcia-Segura, LM; 2009[2] Betley, JN, et al.; (2013)[3] Muller, TD, et al.; (2015)