Illuminating the Metabolic Function of GPR162 by Delineating Downstream Signaling Pathways and Characterizing Hypothalamic Expression Pattern

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PROJECT SUMMARY Of the twenty thousand proteins encoded in the human genome, three thousand of them are considered as part of the `druggable genome' by their estimated capability to bind drug-like molecules. Ion channels, kinases and G protein-coupled receptors (GCPRs) are three important components of the `druggable genome'. GPCRs are the most successful class of druggable targets. Currently, GPCRs are the target of over ~26% of the Food and Drug Administration (FDA) approved drugs. GPCRs are a family of seven-transmembrane (7TM) receptors that regulate important physiological functions through a diverse array of the endogenous ligands, which include light, odor, neurotransmitter, ion, hormone, peptide, lipid, metabolite, etc. Yet, despite of their functional importance and excellent druggability, a large number of non-olfactory GPCRs are still understudied, which is largely due to the unknown nature of the endogenous ligands and physiological functions. Therefore, there is an urgent need to characterize the understudies GPCRs by providing new research tools and characterize the physiological function of these receptors. Metabolic diseases, including diabetes and obesity, have become a major health problem worldwide. Sedentary lifestyles and the abundance of palatable and calorie-dense foods in modern societies have undoubtedly contributed to the increasing prevalence of obesity, which is associated with the incidence of multiple co-morbidities including diabetes and cardiovascular diseases. The brain is a key regulator for energy balance, owing to its ability to sense nutrients, control reward/motivation behavior, and orchestrate peripheral responses. The overarching goal of our research program is to understand the molecular mechanisms of neurohormonal pathways critical for feeding and glucose metabolism. Specifically, we aim to focus on the understudied GPCRs in the neuroendocrine system and study their roles in the pathophysiology of obesity and diabetes. Our preliminary study showed that GPR162 expression in the hypothalamus is regulated by feeding conditions and correlated with metabolic derangements. Our data, together with data from the public domain, strongly suggest that more investigations are needed to understand the upstream signals and downstream activities of this understudied GPCR and its relevance to metabolic disease pathophysiology. By characterizing the tissue / cell expression and the signaling properties of this GPCR, we will establish key background knowledge that is necessary to develop developing screening assays and performing pilot screening to obtain agonist and antagonist for GPR162. Moreover, the results from this work will have the potential to translate to humans and to the development of novel therapeutic reagents for metabolic diseases. This complementary expertise of the investigators in GPCR biology and metabolism and the on-going collaboration support the feasibility and increase the likelihood of success. Successful completion of this study will serve as preliminary data for the subsequent NIDDK R01 applications and/or drug discovery projects.