Epigenetic dysregulation of the dopamine system in diet-induced obesity

J. Neurochem. (2012) 120, 891–898. 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. Chronic consumption of a high‐fat diet can alter the expression of dopamine‐related genes; however, the mechanism that drives this response remains unclear. This work identifies differential DNA methylation as a potential link between high‐fat diet and altered gene expression in the brain. A better understanding of the CNS adaptations that occur during the development of obesity will prove critical in designing both better behavioral and pharmacological therapeutics for obesity.