Neuroendocrinology and Neuroimmunology
Author: Lucia Giovanini | Email: luciagiovanini5@gmail.com
Lucia Giovanini1°, Nahuel Wanionok1°, Heredia Florencia1°, Rodriguez Silvia1°, Castrogiovanni Daniel1°, Cornejo Maria Paula1°, Perello Mario1°
1° Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology (IMBICE) (CONICET – CIC-PBA – UNLP)
Liver-expressed antimicrobial peptide 2 (LEAP2) is a newly discovered endogenous ligand of the growth hormone secretagogue receptor (GHSR), a G-protein coupled receptor mainly expressed in the brain that is strongly implicated in the regulation of energy balance. LEAP2 inhibits GHSR activity, including the orexigenic actions of the stomach-derived hormone ghrelin. Here, we used mice to study the kinetics of the inhibitory effect of LEAP2 on ghrelin-induced food intake and the brain nuclei target of this effect. In mice with intracerebroventricular cannulas, we found that centrally-injected LEAP2 blocks the orexigenic effect of ghrelin injected 1-, 3- or 8-h later but does not alter the effect of ghrelin injected 24-h later. We analyzed c-Fos induction in hypothalamic brain nuclei and found that LEAP2 also inhibits ghrelin-induced increase of c-Fos in the arcuate nucleus. We then assessed the ability of a centrally-injected fluorescent variant of LEAP2 (F-LEAP2) to label the brain at different time points. We measured fluorescence intensity of F-LEAP2 labeled neurons, which were mainly localized in the arcuate and ventromedial hypothalamic nuclei. Finally, we performed pulse-chase studies in a HEK 293T cell line that stably expresses GHSR and observed that F-LEAP2 remained bound to GHSR for hours. Altogether, our results suggest that LEAP2 induces a long-term inhibitory effect on the orexigenic effects of ghrelin, presumably because it remains bound to GHSR for several hours.