The orphan receptor GPR68 is expressed in the hypothalamus and is involved in the regulation of feeding.

Currently, up to 35% off all drugs approved for the treatment of human diseases belong to the G-protein-coupled receptor (GPCR) family. Out of the almost 800 existing GPCRs, 25% have no known endogenous ligands and are regarded as orphan receptors; many of these are currently under investigation as potential pharmacological targets. Here, we hypothesised that orphan GPCRs expressed in the hypothalamus could be targets for the treatment of obesity and other metabolic diseases. Using bioinformatic tools, we identified 78 class A orphan GPCRs that are expressed in the hypothalamus of mice. Initially, we selected two candidates and determined their responsivities to nutritional interventions: GPR162, the GPCR with highest expression in the hypothalamus, and GPR68, a GPCR with intermediate expression in the hypothalamus and that has never been explored for its potential involvement in metabolic regulation. GPR162 expression was not modified by fasting/feeding or by the consumption of a high-fat diet, and was therefore not subsequently evaluated. Conversely, GPR68 expression increased in response to the consumption of a high-fat diet and reduced under fasting conditions. Using immunofluorescence, GPR68 was identified in both proopiomelanocortin-expressing and agouti-related peptide-expressing neurons in the hypothalamic arcuate nucleus. Acute inhibition of GPR68 with an allosteric modulator promoted an increase in the expression of the orexigenic agouti-related peptide and neuropeptide Y, whereas 4- and 12-h inhibition of GPR68 resulted in increased caloric intake. Thus, GPR68 has emerged as an orphan GPCR that is expressed in the hypothalamus and is involved in the regulation of feeding.