Obesity and diabetes are growing epidemics that represent major risk factors for the development of cardiovascular diseases and strokes and for which pharmacological treatments are not available. Ghrelin is a hormone secreted by the stomach that acts on tAgouti Related Protein (AGRP) neurons of the hypothalamus, to promote food intake. Deletion of the ghrelin receptor (GHSR1a), a GPCR, in rodents has been shown to prevent diet induced obesity and improve insulin sensitivity. For that reason the GHSR1a is an attractive drug target for the treatment of obesity. The ghrelin system has been prematurely exploited in the past by developing GHSR1a antagonists but the poor bioavailability of those molecules and the lack of understanding of GHSR1a pharmacology has led to poor clinical outcomes. We have recently discovered that GHSR1a interacts with the Melanocortin Receptor Accessory Protein 2 (MRAP2). In the absence of MRAP2, ghrelin does not elicit a signal and does not increase food intake. We have also discovered that MRAP2 inhibits the recruitment of b-arrestin to GHSR1a. b-arrestin recruitment representing one of the main mechanisms that leads to GPCR signaling termination, we hypothesize that the inhibition of b-arrestin recruitment is responsible for the increased ghrelin-stimulated response. We have also identified a residue T261 in the third intracellular loop of GHSR1a that is essential for b-arrestin recruitment. Consequently, we hypothesize that MRAP2 prevents b-arrestin recruitment to GHSR1a by inhibiting the phosphorylation T261. To test those hypothesis we will use a combination of biochemical and behavioral experiments in genetically modified mouse models. We will determine if MRAP2 decreases GHSR1a phosphorylation and if replacing GHSR1a with a mutated GHSR1aT261A defective for b-arrestin recruitment eliminates the requirement for MRAP2 for the orexigenic action of ghrelin. We will also test if silencing the expression of b-arrestins in AGRP neurons has the same outcome. Completion of these experiments will identify the mechanism of MRAP2-mediated regulation of GHSR1a and determine if preventing the interaction of GHSR1a with MRAP2 is a promising strategy to prevent ghrelin actions and promote weight loss. Such a finding will eliminate the need to target the ligand binding site of GHSR1a which has proven challenging in the past and offer new targets within the interface of GHSR1a and MRAP2 for future drug development efforts.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|