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Diabetologia. 2017 Aug;60(8):1502-1511. doi: 10.1007/s00125-017-4305-4. Epub 2017 May 20.

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.

Author information

1
Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Medicine), Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Nakagami-gun, Okinawa, 903-0215, Japan.
2
Department of Genome Medicine, National Research Institute for Child Health and Development, Tokyo, Japan.
3
Department of Molecular Anatomy, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
4
Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
5
Department of Molecular and Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
6
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
7
Kanagawa Academy of Science and Technology, Kanagawa, Japan.
8
Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Medicine), Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Nakagami-gun, Okinawa, 903-0215, Japan. hiroaki@med.u-ryukyu.ac.jp.

Abstract

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 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.

METHODS:

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.

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 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/INTERPRETATION:

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.

KEYWORDS:

DNA methylation; Dopamine; Epigenetics; Feeding behaviour; Nutrition; Obesity; Reward; Striatum; Type 2 diabetes

PMID:
28528402
PMCID:
PMC5491592
DOI:
10.1007/s00125-017-4305-4
[Indexed for MEDLINE]
Free PMC Article

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