Olfactory receptor 43 reduces hepatic lipid accumulation and adiposity in mice |
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| Affiliation: | 1. Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria;2. Institute of Molecular Biosciences, University of Graz, Graz, Austria;3. Center for Medical Research, Medical University of Graz, Graz, Austria;4. Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria;5. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria;6. Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria;7. BioTechMed-Graz, Graz, Austria;1. Department of Biochemistry and Functional Proteomics, Faculty of Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestr. 1, 79104 Freiburg, Germany;2. Department of Cell Physiology, Ruhr-Universität Bochum, Universitätsstrasse 150, 44780 Bochum, Germany;3. Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., Otto-Hahn-Str. 6b, 44227 Dortmund, Germany;4. Department of Pharmacology and Toxicology, University of Jena, Drackendorfer Str. 1, 07747 Jena, Germany |
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| Abstract: | Olfactory receptors are primarily expressed in nasal olfactory epithelium, but these receptors are also ectopically expressed in diverse tissues. In this study, we investigated the biological functions of Olfr43, a mouse homolog of human OR1A1, in cultured hepatocytes and mice to assess its functionality in lipid metabolism. Olfr43 was expressed in mouse hepatocytes, and Olfr43 activation by a known ligand, (−)-carvone, stimulated cAMP response element-binding protein (CREB) activity. In ligand-receptor binding studies using site-directed mutagenesis, (−)-carvone binding required two residues, M257 and Y258, in Olfr43. In the mouse study, oral administration of (−)-carvone for 5 weeks in high-fat diet-fed mice improved energy metabolism, including reductions in hepatic steatosis and adiposity, and improved glucose and insulin tolerance. In mouse livers and cultured mouse hepatocytes, Olfr43 activation simulated the CREB-hairy and enhancer of split 1 (HES1)-peroxisome proliferator-activated receptor (PPAR)-γ signaling axis, leading to a reduction in hepatic triglyceride accumulation in the mouse liver. Thus, long-term administration of (−)-carvone reduces hepatic steatosis. The knockdown of Olfr43 gene expression in cultured hepatocytes negated these effects of (−)-carvone. In conclusion, an ectopic olfactory receptor, hepatic Olfr43, regulates energy metabolism via the CREB-HES1-PPARγ signaling axis. |
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