Epigenetic dysregulation of the dopamine system in diet-induced obesity.
Chronic intake of high-fat (HF) diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to HF diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry [ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)], critical for coding the rewarding properties of palatable food and important in hedonically driven feeding behavior. Using a mouse model of diet-induced obesity (DIO), significant alterations in the expression of DA-related genes were documented in adult animals, and the general pattern of gene expression changes was opposite within the hypothalamus versus the reward circuitry (increased vs. decreased, respectively). Differential DNA methylation was identified within the promoter regions of tyrosine hydroxylase (TH) and dopamine transporter (DAT), and the pattern of this response was consistent with the pattern of gene expression. Behaviors consistent with increased hypothalamic DA and decreased reward circuitry DA were observed. These data identify differential DNA methylation as an epigenetic mechanism linking the chronic intake of HF diet with altered DA-related gene expression, and this response varies by brain region and DNA sequence.
Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
Zivjena
Z
Vucetic
Jesse Lea
JL
Carlin
Kathy
K
Totoki
Teresa M
TM
Reyes
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D057890:Epigenomics / Q000379:methods*; D005786:Gene Expression Regulation / Q000235:genetics*; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology* / Q000473:pathology; D012333:RNA, Messenger; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D004041:Dietary Fats; D050483:Dopamine Plasma Membrane Transport Proteins; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D014446:Tyrosine 3-Monooxygenase; D002394:Catechol O-Methyltransferase; D004298:Dopamine