PROJECT SUMMARY/ABSTRACT The incidence of obesity and related disorders including diabetes mellitus continue to rise. Chronic over nutrition is prevalent, which has profound metabolic effects including causing increased systemic inflammation and altered hepatic glucose and lipid production. Research into the molecular mechanisms underlying energy balance are important for developing new prevention strategies, diagnostic tests and treatments in chronic metabolic diseases such as obesity and diabetes. Notably, our emphasis on a G-protein coupled receptor (GPCR) may lead to the development of novel pharmaceutical therapies, as these are currently the most heavily investigated receptor groups for drug target development. Specifically, GPR149 is an orphan GPCR about which very little is known in terms of body distribution and physiological role(s). However, our laboratory has recently found that Gpr149 is highly expressed in a brain circuit involved in the regulation of energy homeostasis and feeding. Hence, our data support the hypothesis that neuronal GPR149 links an unknown metabolic cue to the neural pathways controlling energy homeostasis. Notably, using the CRISPR-Cas9 technology, we have generated a novel mouse model allowing the deletion of endogenous Gpr149 expression in a tissue-specific manner. Using this mouse model, our proposal will directly assess the physiological role of neuronal GPR149 in energy balance. Ultimately, the data generated under this RFA will be findable through Pharos and serve as a basis for future efforts aimed at understanding the basic role of GPR149 signaling.

PROJECT NARRATIVE GPR149 is an orphan receptor about which very little is known. We anticipate that studies proposed within this application may lay the groundwork for a future studies aimed at understanding the exact mechanisms linking GPR149 and the neural control of energy balance in the mouse. In addition, the work proposed in this grant will result in the validation and characterization of a novel mouse model (already generated in our group) and Gpr149 antibody which will be of interest to many scientists interested by understudied IDG-eligible receptors.