Session: 3

PS3-09 | Dissecting the putative differential roles of ghrelin-evoked versus constitutive growth hormone secretagogue receptor (GHSR) activity in mouse models

Maria Paula Cornejo

Neurophysiology Lab / IMBICE / CONICET-CIC-UNLP

The growth hormone secretagogue receptor (GHSR) is a G-protein coupled receptor highly expressed in the brain that mediates the action of the stomach-derived hormone ghrelin. In addition, in vitro studies have shown that GHSR displays a very high constitutive activity, whose physiological function remains uncertain. Here, we studied mice with genetic or pharmacological manipulations of GHSR in order to clarify the putative role of GHSR constitutive activity in vivo. First, we investigated mice harboring a mutant version of GHSR that lacks constitutive activity (GHSR-mut mice). We found that GHSR-mut mice show daily food intake and body weight similar to wild-type (WT) mice but did not increase food intake nor the expression of the marker of neuronal activation c-Fos in the hypothalamus in response to ghrelin. Also, GHSR-mut mice show high fat diet (HFD) intake in a binge eating protocol similar to WT mice, in contrast to GHSR-deficient mice which display reduced intake of HFD. Additionally, we assessed the effects of the selective GHSR inverse agonist PF-5190457 in mice. We found that PF-5190457 reduces the effects of ghrelin treatment on both food intake and c-Fos expression in the hypothalamus. Also, PF-5190457 reduced HFD intake in WT mice exposed to the binge eating protocol, while it was ineffective in GHSR-deficient mice. Thus, current results indicate that unmasking differential roles of ghrelin-evoked vs. constitutive GHSR activity in vivo is extremely challenging.