N‑Terminal Liver-Expressed Antimicrobial Peptide 2 (LEAP2) Region Exhibits Inverse Agonist Activity toward the Ghrelin Receptor

The ghrelin receptor
or growth hormone secretagogue receptor (GHSR)
is a G-protein-coupled receptor that controls growth hormone and insulin
secretion, food intake, and reward-seeking behaviors. Liver-expressed
antimicrobial peptide 2 (LEAP2) was recently described as an endogenous
antagonist of GHSR. Here, we present a study aimed at delineating
the structural determinants required for LEAP2 activity toward GHSR.
We demonstrate that the entire sequence of LEAP2 is not necessary
for its actions. Indeed, the N-terminal part alone confers receptor
binding and activity to LEAP2. We found that both LEAP2 and its N-terminal
part behave as inverse agonists of GHSR and as competitive antagonists
of ghrelin-induced inositol phosphate production and calcium mobilization.
Accordingly, the N-terminal region of LEAP2 is able to inhibit ghrelin-induced
food intake in mice. These data demonstrate an unexpected pharmacological
activity for LEAP2 that is likely to have an important role in the
control of ghrelin response under normal and pathological conditions.