246 | LEAP2 has greater accessibility and longer lasting effects than ghrelin in the mouse brain

Neuroendocrinology and Neuroimmunology

Author: Lucia Giovanini | Email: luciagiovanini5@gmail.com

Lucia Giovanini , María Paula Cornejo , Guadalupe Garcia Romero , Daniel Castrogiovanni , Mario Perelló

1° Laboratory of Neurophysiology – Multidisciplinary Institute of Cell Biology (CONICET/CICPBA/UNLP), La Plata, Argentina
2° 2Department of Surgical Sciences, Functional Pharmacology and Neuroscience – University of Uppsala, Sweden

Liver-expressed antimicrobial peptide 2 (LEAP2) is a newly discovered hormone that acts via the growth hormone secretagogue receptor (GHSR) and impairs the actions of ghrelin, a stomach-derived orexigenic hormone. Here, we used mice to study the extent to which LEAP2 reaches the hypothalamus and the neuronal circuits engaged by LEAP2 to antagonize ghrelin’s orexigenic effect. First, we confirmed that centrally-injected LEAP2 decreases overnight food intake and body weight as well the orexigenic effect of simultaneously-injected ghrelin. Then, we studied the kinetics of the inhibitory effect of LEAP2 on ghrelin-induced food intake, and found that centrally-injected LEAP2 blocks the orexigenic effect of ghrelin injected 1-, 3- or 8-h later but not the effect of ghrelin injected 24-h later. Also, we assessed the ability of a centrally-injected fluorescent variant of LEAP2 (F-LEAP2) to label the brain at different time points, and found that F-LEAP2 labeled neurons, which were mainly localized in the arcuate nucleus, even 3-h after injection. We also incubated the external side of hypothalamic explants with F-LEAP2 or fluorescent ghrelin, and found that F-LEAP2 showed greater diffusion into the tissue than fluorescent ghrelin. Altogether, our results suggest that 1) LEAP2 induces a long-term inhibitory effect on the orexigenic effects of ghrelin, presumably because it remains bound to GHSR, and 2) LEAP2 displays a greater accessibility to the brain than ghrelin.