Dr. Julien Sebag, Assistant Professor of Molecular Physiology and Biophysics and member of the FOEDRC was recently awarded a 5-year $1.9M grant from the NIDDK for a project entitled: Investigating the requirement of MRAP2 for ghrelin function.
The project studies the “hunger hormone” ghrelin, which is mainly secreted by the stomach during periods of fasting to signal hunger to the brain. Ghrelin regulates food intake and energy expenditure by acting at its receptor the Growth Hormone Secretagogue Receptor 1a (GHSR1a). The effect of ghrelin on food intake and energy homeostasis are mediated centrally in the hypothalamus, through the activation of the hunger sensing AGRP/NPY neurons. Genetic models that lack GHSR1a in all cells or in the hypothalamus are protected from diet-induced obesity. Thus, GHSR1a is a promising target for the treatment of obesity and blockers of the ghrelin receptor have been developed for this purpose. However, these drugs bind to receptors in multiple organs and are not very well absorbed, representing challenges which have precluded them from being used in the clinic. New compounds with improved chemical properties and better in-vivo efficacy could likely be identified by using more relevant drug discovery strategies. Improvement of screening strategies requires a better understanding of GHSR1a regulation. Dr. Sebag’s laboratory recently discovered that the hunger effect of ghrelin is lost in mice in which the Melanocortin Receptor Accessory Protein 2 (MRAP2) was genetically removed. Early studies demonstrate that MRAP2 interacts with GHSR1a and strongly increases its activity. Additionally, they showed that MRAP2 is expressed in the ghrelin responsive AGRP/NPY neurons. Consistent with those findings, Sebag and colleagues found that AGRP neurons from MRAP2 deficient mice fail to activate in response to fasting. The goals of the proposed project are to identify the role of MRAP2 in promoting ghrelin signaling and the response of AGRP neurons to starvation. The project also seeks to understand the molecular mechanisms through which MRAP2 enhances the efficacy of GHSR1a signaling. Successful completion of the proposed project will provide fundamental information on the role and mechanism of action of MRAP2 in AGRP neurons as it pertains to ghrelin functions. It will also advance our understanding of AGRP neuron regulation and the hypothalamic control of energy homeostasis. This research will generate new knowledge on the regulation of hormone receptors by accessory proteins and identify MRAP2 as a novel energy sensor. The knowledge derived from the proposed experiments will likely enable the design of more physiologically relevant model systems for drug discovery strategies targeting ghrelin signaling. It is anticipated that successful completion of these studies may lead to new and better drug treatments for obesity. Congratulations Julien!