Chronic High-Fat Diet Drives Postnatal Epigenetic Regulation of m-Opioid Receptor in the Brain

Author(s): Zivjena Vucetic, Jessica Kimmel and Teresa M Reyes
 

Abstract

Opioid system dysregulation has been observed in both genetic and high-fat diet (HFD)-induced models of obesity. An understanding of the molecular mechanisms of MOR transcriptional regulation, particularly within an in vivo context, is lacking. Using a diet-induced model of obesity (DIO), mice were fed a high-fat diet (60% calories from fat) from weaning to >18 weeks of age. Compared with mice fed the control diet, DIO mice had a decreased preference for sucrose. MOR mRNA expression was decreased in reward-related circuitry (ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC)) but not the hypothalamus, important in the homeostatic regulation of feeding. DNA methylation is an epigenetic modification that links environmental exposures to altered gene expression. We found a significant increase in DNA methylation in the MOR promoter region within the reward-related brain regions. Methyl CpG-binding protein 2 (MeCP2) can bind methylated DNA and repress transcription, and DIO mice showed increased binding of MeCP2 to the MOR promoter in reward-related regions of the brain. Finally, using ChIP assays we examined H3K9 methylation (inactive chromatin) and H3 acetylation (active chromatin) within the MOR promoter region and found increased H3K9 methylation and decreased H3 acetylation. These data are the first to identify DNA methylation, MeCP2 recruitment, and chromatin remodeling as mechanisms leading to transcriptional repression of MOR in the brains of mice fed a high-fat diet.

Commentary

by Teresa Reyes
Reward hypofunction has been observed in both obese human subjects and animal models of obesity, and it has been suggested that reduced function of the reward system can lead to an increased motivation to consume palatable foods. Reward hypofunction has been linked to alterations in dopamine system functioning, and in this report, we investigated whether the opioid system (also important in coding reward) was altered in obesity. Using a mouse model of diet-induced obesity (chronic exposure to a high fat diet), obese mice showed a decreased expression of µ-opioid receptor (MOR) mRNA in regions of the brain associated with reward (ventral tegmental area, nucleus accumbens and prefrontal cortex). We were then interested in asking whether epigenetic mechanisms of gene regulation were involved in driving the decrease in MOR expression. We found that decreased MOR mRNA was associated with epigenetic changes suggestive of a repressed transcriptional state at the histone and DNA level (DNA hypermethylation within the promoter region of MOR, increased binding of MeCP2 within the active promoter region of the MOR, an increase in H3-K9 methylation and a decrease in H3 acetylation). Collectively, these data identify postnatal epigenetic regulation of MOR repression as a CNS response to the chronic intake of high fat diet; a response which may, among other things, contribute to the difficulty in establishing healthier eating patterns after chronic exposure to highly palatable foods.

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