Impact of brown rice-specific γ-oryzanol on epigenetic modulation of dopamine D2 receptors in brain striatum in high-fat-diet-induced obesity in mice

Aims/hypothesis Overeating of dietary fats causes obesity in humans and rodents. Recent studies in humans and rodents have demonstrated that addiction to fats shares a common mechanism with addiction to alcohol, nicotine and narcotics in terms of a dysfunction of brain reward systems. It has been highlighted that a high-fat diet (HFD) attenuates dopamine D2 receptor (D2R) signalling in the striatum, a pivotal regulator of the brain reward system, resulting in hedonic overeating. We previously reported that the brown rice-specific bioactive constituent gamma-oryzanol attenuated the preference for an HFD via hypothalamic control. We therefore explored the possibility that gamma-oryzanol would modulate functioning of the brain reward system in mice. Methods Male C57BL/6J mice fed an HFD were orally treated with gamma-oryzanol, and striatal levels of molecules involved in D2R signalling were evaluated. The impact of gamma-oryzanol on DNA methylation of the D2R promoter and subsequent changes in preferences for dietary fat was examined. In addition, the effects of 5-aza-2'-deoxycytidine, a potent inhibitor of DNA methyltransferases (DNMTs), on food preference, D2R signalling and the levels of DNMTs in the striatum were investigated. The inhibitory effects of gamma-oryzanol on the activity of DNMTs were enzymatically evaluated in vitro. Results In striatum from mice fed an HFD, the production of D2Rs was decreased via an increase in DNA methylation of the promoter region of the D2R. Oral administration of gamma-oryzanol decreased the expression and activity of DNMTs, thereby restoring the level of D2Rs in the striatum. Pharmacological inhibition of DNMTs by 5-aza-2'-deoxycytidine also ameliorated the preference for dietary fat. Consistent with these findings, enzymatic in vitro assays demonstrated that gamma-oryzanol inhibited the activity of DNMTs. Conclusions/interpretation We demonstrated that gamma-oryzanol ameliorates HFD-induced DNA hypermethylation of the promoter region of D2R in the striatum of mice. Our experimental paradigm highlights gamma-oryzanol as a promising antiobesity substance with the distinct property of being a novel epigenetic modulator