CART‐GPR160 Regulation of Food Intake

Abstract

Cocaine and amphetamine regulated transcript (CART) mRNA was identified in 1995 as a novel transcript increased in the striatum after acute cocaine or amphetamine administration. This transcript matched the protein sequence of an Ovine hypothalamic peptide partially sequenced by Spiess and Vale in 1981, implying that this transcript was indeed translated into an active peptide product. CART peptide is a multifunctional neuromodulator with roles in pain, reward, addiction, and food intake. Using our deductive reasoning strategy (Yosten et al. AJP303:R941, 2012) we have identified the previously orphaned G‐protein coupled receptor, GPR160, as a candidate CART receptor. Colocalization, proximity ligation, and immunoprecipitation studies have confirmed the association of CART and GPR160. We translated this evidence into in vivo rat food intake studies. The action of CART to inhibit food intake (4V administration) was lost in animals pre‐treated with siRNA targeting the GPR160 transcript. Additionally, passive immunoneutralization of GPR160 achieved by injecting antibody against the second extracellular loop of GPR160 into the fourth ventricle also blocked the anorexic effects of pharmacologic doses of fourth ventricle CART peptide. Taken together, these data identify GPR160 as a necessary component of the CART peptide signaling pathway and further demonstrate the requirement for this interaction to mediate the food intake reducing effects of CART peptide. Research on the function of CART peptide had been severely hindered by the lack of knowledge of a cognate receptor. The discovery of a CART peptide receptor will not only revitalize research in the CART field, but also potentially lead to novel therapeutic agents for the treatment of obesity and pain management.Support or Funding InformationHL121456This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.