Impact of brown rice-specific \u03b3-oryzanol on epigenetic modulation of dopamine D2 receptors in brain striatum in high-fat-diet-induced obesity in mice

Chisayo Kozuka,Keiko Abe,Masayuki Matsushita,Tadashi Kaname,Masato Tsutsui,Chigusa Shimizu-Okabe,Chitoshi Takayama,Hiroaki Masuzaki

doi:10.1007/s00125-017-4305-4

Abstract

Aims/hypothesisOvereating 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 γ-oryzanol attenuated the preference for an HFD via hypothalamic control. We therefore explored the possibility that γ-oryzanol would modulate functioning of the brain reward system in mice.MethodsMale C57BL/6J mice fed an HFD were orally treated with γ-oryzanol, and striatal levels of molecules involved in D2R signalling were evaluated. The impact of γ-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 γ-oryzanol on the activity of DNMTs were enzymatically evaluated in vitro.ResultsIn 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 γ-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 γ-oryzanol inhibited the activity of DNMTs.Conclusions/interpretationWe demonstrated that γ-oryzanol ameliorates HFD-induced DNA hypermethylation of the promoter region of D2R in the striatum of mice. Our experimental paradigm highlights γ-oryzanol as a promising antiobesity substance with the distinct property of being a novel epigenetic modulator.

Highlights

Overeating in obese individuals shares, at least partly, common mechanisms with addiction to alcohol, nicotine and narcotics [1]
The major finding in the present study is that γ-oryzanol acts as a potent DNA methyltransferases (DNMTs) inhibitor in the striatum of mice, thereby attenuating, at least partly, the preference for an high-fat diet (HFD) via the epigenetic modulation of striatal D2 receptor (D2R)
In striatum from HFD-fed mice, levels of D2R were significantly decreased, whereas those of D1R, tyrosine hydroxylase (TH) and dopamine transporter (DAT) were not changed (Fig. 1b–e, k–m). These data are consistent with the notion that dysregulation of striatal D2R plays a critical role in the perception of food reward when on an HFD, leading to hedonic overconsumption of HFD in obese animals [3]

Summary

Introduction

Overeating in obese individuals shares, at least partly, common mechanisms with addiction to alcohol, nicotine and narcotics [1]. Because of the reduced D2R density, the dorsal striatum is less responsive to food reward compared with lean control groups in obese humans and rodents [3,4,5] In accordance with this notion, the TaqIA allele of the ANKK1 gene locus (encoding DRD2/ankyrin repeat and kinase domain containing 1), which decreases striatal D2R production, is associated with an obese phenotype in humans [6], while the effects of weight loss after bariatric surgery are associated with elevated striatal D2R density [7]. These data strongly suggest the importance of striatal D2R as a novel therapeutic target for the treatment of obesity. Some drugs that were developed that acted on the brain reward system caused considerable adverse effects, including serious psychiatric problems, resulting in their eventual withdrawal from clinics [8]

Methods

Results

Conclusion