Ectopic OR1A1 activation ameliorates hepatic lipid deposition through AMPK/SREBP-1/FASN pathway by three monoterpenes

[Display omitted] •Monoterpenes ameliorated body weight, blood lipids and insulin resistance in HFD-fed mice.•Monoterpenes attenuated hepatic lipid accumulation via AMPK/SREBP1/FASN pathway.•Monoterpenes alleviated lipid deposition in LO2 cells induced by FFAs dependently on OR1A1.•OR1A1 could be a potential target for counteracting hepatic steatosis. Ectopic olfactory receptors, such as OR1A1, are involved in the regulation of lipid metabolism homeostasis. In this study, we investigated the effects of three monoterpenes, (+)-limonene, (−)-carvone and thymol, upon hepatic lipid deposition. Oral administration of (+)-limonene, (−)-carvone and thymol for 8 weeks in high-fat-diet (HFD)-fed mice significantly lowered the levels of fasting blood glucose, improved glucose intolerance, serum lipid parameters, adiposity, and hepatic steatosis. In LO2 cells, (+)-limonene, (−)-carvone and thymol increased the cyclic adenosine monophosphate (cAMP), induced protein kinase A (PKA) activity and phosphorylation of AMPK, downregulated the expression of SREBP-1 and FASN, and eventually led to a reduction in hepatic lipid deposition. Meanwhile, these beneficial effects in cultured LO2 cells were negated by OR1A1 knockdown and the adenylyl cyclase inhibitor SQ22536, respectively, indicating that they can ameliorate disorders of lipid metabolism through activating OR1A1 and subsequent AMPK/SREBP-1/FASN pathway, indicating OR1A1 as a potential target for counteracting hepatic steatosis.