Epigenetic memory of chronic exposure to high fat diet in reward-associated CNS circuitry
Sunday, Nov 14, 2010, 2:00 PM - 3:00 PM
, T. M. REYES
Dept. of Pharmacol., Univ. of Pennsylvania, PHILADELPHIA, PA;
Univ. of Pennsylvania, Philadelphia, PA
Regulation of gene expression in response to environmental stimuli (such as nutrition or drugs of abuse) can be achieved via epigenetic mechanisms that modify regulatory DNA regions (cytosine methylation) or alter histone structure (methylation, acetylation). Using a mouse model, we have previously found that 15-week exposure to 60% high fat (HF) diet induces epigenetic silencing (specifically, increased DNA methylation and histone H3-Lys9 methylation and decreased H3-Lys acetylation) of tyrosine-hydroxylase (TH), dopamine reuptake transporter (DAT) and mu-opioid receptor (MOR) genes in brain regions associated with reward (nucleus accumbens (NAC), ventral tegmental area (VTA), prefrontal cortex (PFC) and hypothalamus). The goal of this study was to assess the reversibility of these HF-diet induced epigenetic changes after withdrawal from HF diet. Dietary-induced obese mice (n= 8-10/group) were removed from HF diet and placed on control diet for 1, 2, and 4 weeks. At the end of each time point, gene expression (by real-time PCR) and epigenetic analysis (using chromatin (ChIP) and methyl-DNA (MeDIP) immunoprecipitation assays) were performed in microdissected brain regions. Reduced expression of TH, DAT and MOR observed in DIO-animals starts to reverse after 2 weeks of dieting but does not reach the levels seen in controls even after 4 weeks. At the same time (2 weeks on control diet) we observed an increase in H3-Lys4 acetylation suggesting partial reactivation of epigenetically repressed state of TH, DAT and MOR promoters in obese mice. In contrast, during the 4 weeks of dieting, promoters of TH, DAT and MOR genes remain hypermethylated in reward-associated regions (NAC, VTA and PFC) as assessed by MeDIP analysis. These studies suggest that long-term exposure to high-fat diet has permanent effects of on gene regulatory mechanisms that mediate reward and could not be easily reversed by dieting alone. Epigenetic changes in brain-associated genes may represent a form of molecular memory of nutritional insults that could ultimately have long-term effects on dysregulation of reward-related behaviors in obesity.
NIH Grant MH087978
[Authors]. [Abstract Title]. Program No. XXX.XX. 2010 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2010. Online.
2010 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.
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