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.
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.
复制标题
DOI：
10.1007/s00125-017-4305-4
复制
发表时间：
2017-08
期刊：
影响因子：
8.2
通讯作者：
Masuzaki H
中科院分区：
文献类型：
--
作者：
Kozuka C;Kaname T;Shimizu-Okabe C;Takayama C;Tsutsui M;Matsushita M;Abe K;Masuzaki H
饮食脂肪过量导致人类和啮齿动物肥胖。最近对人类和啮齿动物的研究表明，脂肪成瘾与酒精、尼古丁和麻醉品成瘾在大脑奖励系统功能障碍方面有着共同的机制。已经强调的是，高脂肪饮食（HFD）减弱纹状体中的多巴胺D2受体（D2 R）信号传导，纹状体是大脑奖励系统的关键调节器，导致享乐性暴饮暴食。我们先前报道，糙米特异性生物活性成分γ-谷维素通过下丘脑控制减弱了对HFD的偏好。因此，我们探索了γ-谷维素调节小鼠大脑奖励系统功能的可能性。喂食HFD的雄性C57 BL/6 J小鼠经口给予γ-谷维素，并评估参与D2 R信号传导的分子的纹状体水平。研究了γ-谷维素对D2 R启动子DNA甲基化的影响以及随后对膳食脂肪偏好的变化。此外，研究了DNA甲基转移酶（DNMTs）的有效抑制剂5-氮杂-2 ′-脱氧胞苷对食物偏好、D2 R信号传导和纹状体中DNMTs水平的影响。体外酶法测定γ-谷维素对DNMT活性的抑制作用。在来自喂食HFD的小鼠的纹状体中，D2 R的产生通过D2 R的启动子区域的DNA甲基化的增加而减少。口服γ-谷维素降低了DNMT的表达和活性，从而恢复了纹状体中D2 Rs的水平。5-氮杂-2 ′-脱氧胞苷对DNMT的药理学抑制作用也改善了对膳食脂肪的偏好。与这些发现一致，体外酶促测定表明γ-谷维素抑制DNMT的活性。我们证明，γ-谷维素改善HFD诱导的小鼠纹状体D2 R启动子区域的DNA超甲基化。我们的实验范式突出了γ-谷维素作为一种有前途的抗肥胖物质，具有作为一种新型表观遗传调节剂的独特性质。本文的在线版本（doi：10.1007/s 00125 -017-4305-4）包含同行评审但未经编辑的补充材料，可供授权用户使用。
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 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. Male 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. 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 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. We 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. The online version of this article (doi:10.1007/s00125-017-4305-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.