Olfactory receptors (ORs) are classic GPCRs primarily expressed in the olfactory epithelium, where they transmit real-time sensory signals to the brain. However, they are also expressed in multiple non-olfactory tissues like brain, gut, muscle etc., which often has been described as ectopic expression. Elucidation of the physiological roles of these ectopic receptors is revealing therapeutic potential in several conditions including obesity. Indeed, the results from our collaboration with Circuit Therapeutics suggest an important role of the ectopic expressed OR51T1 mouse homologue Olfr544 in body weight regulation. This orphan OR is located in the glutamatergic Area postrema (AP) brainstem circuitry. The AP specific overexpression of Olfr574 in lean mice leads to resistance against weight gain over 7 weeks caused by high fat diet. Surprisingly these mice showed no effect on food intake and high fat preference. To test the involvement of Olfr674 further, we used complementary manipulations (shRNA) to generate AP specific Olfr574-KO mice. These mice exhibit increased body weight in the absence of any change in food intake and high fat diet. Together, these observations demonstrate Olfr574 is involved in regulation of body weight effects and further suggest the human homologue OR51T1 as a possible target for treating obesity in humans. Next steps will include the de-orphanization of the human OR51T1 and murine Olfr574 as well as ligand structure improvement and selectivity-screening of ligands against an OR-library in order to further validate the role of OR51T1 in obesity.
K. Bleymehl: None.
