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

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

SUBMITTER: Kozuka C

PROVIDER: S-EPMC5491592 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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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.

Kozuka Chisayo C Kaname Tadashi T Shimizu-Okabe Chigusa C Takayama Chitoshi C Tsutsui Masato M Matsushita Masayuki M Abe Keiko K Masuzaki Hiroaki H

Diabetologia 20170520 8

<h4>Aims/hypothesis</h4>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 previ ...[more]

PMID: 28528402

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Project description:Background:A high-fat diet (HFD) can induce obesity and metabolic disorders that are closely associated with cognitive impairments, and the progression of several psychiatric disorders such as anxiety. We have previously demonstrated the anxiolytic-like effect of Gamma oryzanol (GORZ) in chronic restraint stressed mice. Objective:We studied the neurochemical and molecular mechanisms that underlie the preventive effect of GORZ in HFD-induced anxiety-like behaviors, monoaminergic dysfunction, and inflammation. Methods:Eight-week-old Institute of Cancer (ICR) male mice weighing 33-34 g were divided into the following groups and free-fed for 8 weeks: control (14% casein, AIN 93M); HFD; HFD + GORZ (0.5% GORZ). Body weight gain was checked weekly. The anxiolytic-like effects of GORZ were examined via open-field test (OFT) and elevated plus maze (EPM) test. Brain levels of monoamines [5-hydroxy tryptamine (5-HT), dopamine (DA), and norepinephrine (NE)] and their metabolites [5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], proinflammatory cytokines such as tumor necrosis factor-?? (Tnf-?) mRNA levels, and interleukin 1-? (Il-1?) mRNA levels in the cerebral cortex and amygdala were examined using high-performance liquid chromatography-electrochemical detection (HPLC-ECD), and real-time reverse transcription-polymerase chain reaction (RT-PCR), respectively. Results:Mice fed a HFD for eight weeks showed anxiety-like behaviors in association with HFD-induced body weight gain. GORZ potentially blocked HFD-induced anxiety-like behaviors via significant improvement of the primary behavioral parameters in behavioral tests, with a minor reduction in HFD-induced body weight gain. Furthermore, GORZ treatment significantly downregulated HFD-induced upregulation of dopamine levels in the brain's amygdala. Significant reduction of the relative mRNA expression of Tnf-? and Il-1 ? was also observed in the amygdala of HFD + GORZ mice, compared to HFD mice. Conclusions:Our findings strongly suggest that 0.5% GORZ exerts anxiolytic-like effects, possibly through downregulation of dopamine, and via expression of proinflammatory cytokines Tnf-? and Il-1 ? in the case of chronic HFD exposure.

Dataset Information

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

Publications

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.

Similar Datasets

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