HOR1-C59, Or5v1/Olfr110 Gs-Agonist

HOR1-C59 is a cell-permeable, stable and highly selective full agonist of the ectopic olfactory receptor Or5v1/Olfr110, exhibiting approximately 2-fold greater potency than the endogenous oxylipin 12(S)-HEPE (EC50 ≈ 7.12 nM). Mechanistically, HOR1-C59 selectively drives Gs-protein coupling to trigger the cAMP-PKA cascade in hepatocytes, resulting in the robust phosphorylation (Thr51/Thr53) and nuclear translocation of transcription factor ATF2. Once in the nucleus, ATF2 binds the Cpt1α promoter (-1761 to -2000 bp region) to upregulate the expression of Cpt1α. Through this direct engagement of mitochondrial β-oxidation machinery, HOR1-C59 effectively reverses diet-induced obesity, hepatic steatosis, and insulin resistance in an Olfr110-dependent manner.