Standard and High Fat Food Intake is Suppressed by PF5190457, the Ghrelin Growth Hormone Secretagogue 1α Receptor Inverse Agonist/Antagonist

Abstract

Ghrelin is a 28‐amino acid peptide produced by epithelial cells in the stomach mucosa and is well‐characterized to modulate gastrointestinal function, growth hormone secretion, glucose regulation, and appetite, and is increasingly implicated in substance use disorder (SUD) phenotypes. Ghrelin actions are transduced through the growth hormone secretagogue receptor 1α (GHS1αR) which is noted to exhibit constitutive activity in in vitro recombinant cell lines, and in dispersed pancreas islet cells, studies which support the concept of endogenous ghrelin tone. The small molecule PF5190457 exhibits relatively equipotent actions as a neutral GHS1αR antagonist and inverse agonist without apparent partial agonist actions (Kong et al. Br J Pharmacol 173:1452, 2016). To expand our knowledge of the physiological impact of GHS1αR function in vivo and determine an effective dose of PF5190457 for future studies of SUD phenotypes, we tested the hypotheses that PF5190457 would antagonize GHS1αR agonist‐induced intake of standard chow (SD) or high fat food (HFF) and act as an inverse agonist to inhibit basal HFF intake and weight gain.MethodsMale Sprague‐Dawley rats (n=16) maintained on ad libitum SD were pretreated with intraperitoneal injection of PF5190457 (20 mg/kg) or vehicle 60 min prior to subcutaneous (SC) injection of the GHS1αR agonist hexarelin (80 μg/kg) and assay of SD intake over a 6‐hr period. In a second study, rats (n=32) were administered acute or repeated PF5190457 (20 mg/kg) prior to maintenance on ad libitum HFF for three days. On day 3, all rats were treated with PF5190457 or vehicle 60 min prior to hexarelin (80 μg/kg; SC). Food intake and body weight were recorded throughout the study.ResultsPF5190457 significantly suppressed hexarelin‐induced SD intake vs. vehicle (p < 0.05). Both acute and repeated PF5190457 administration suppressed hexarelin‐induced HFF intake vs. control (p < 0.05). Repeated PF5190457 suppressed basal HFF intake and body weight gain (p < 0.05).ConclusionsThe novel GHS1αR inverse agonist/antagonist PF5190457 suppressed measures of both hexarelin‐induced SD and HFF intake, demonstrating antagonist activity in vivo. Similar efficacy of acute and repeated PF5190457 to suppress hexarelin‐induced HFF intake suggests that tolerance did not develop. Further, PF5190457 suppressed basal HFF intake and HFF‐associated weight gain, indicating inverse agonist activity in vivo. Together, these data suggest that PF5190457 will be a useful pharmacological tool to study the involvement of GHS1αR in SUD phenotypes.Support or Funding InformationSupported by NIDA UG3 DA050317 and F30 DA049501