Maternal High-Fat Diet Alters Methylation and Gene Expression of Dopamine and Opioid-Related Genes

TLDR

Maternal obesity during pregnancy raises offspring obesity risk, and energy‑dense high‑fat foods drive obesity while dopamine and opioid reward circuits influence food preference; epigenetic mechanisms also mediate long‑term gene expression changes after in‑utero insults. The study examined how a maternal high‑fat diet alters dopamine and opioid gene expression in offspring mesocorticolimbic reward circuitry and hypothalamus over the long term. A mouse model was used, measuring gene expression by quantitative real‑time PCR in ventral tegmental area, nucleus accumbens, prefrontal cortex, and hypothalamus of offspring exposed to maternal HF diet during pregnancy and lactation. Offspring of HF‑diet dams displayed heightened sucrose and fat preference, up‑regulated DAT in VTA, NAc, and PFC but down‑regulated in hypothalamus, increased MOR and PENK expression in NAc, PFC, and hypothalamus, and global and gene‑specific promoter DNA hypomethylation, linking maternal diet to epigenetic and behavioral changes.

Abstract

Maternal obesity during pregnancy increases the risk of obesity in the offspring. Obesity, arising from an imbalance of energy intake and expenditure, can be driven by the ingestion of palatable [high fat (HF), high sugar], energy-dense foods. Dopamine and opioid circuitry are neural substrates associated with reward that can affect animals’ preference for palatable foods. Using a mouse model, the long-term effect of maternal consumption of a HF diet on dopamine and opioid gene expression within the mesocorticolimbic reward circuitry and hypothalamus of the offspring was investigated. Mice from dams fed a HF diet during pregnancy and lactation showed an increased preference for sucrose and fat. Gene expression, measured using quantitative real-time PCR, revealed a significant approximately 3- to 10-fold up-regulation of dopamine reuptake transporter (DAT) in the ventral tegmental area, nucleus accumbens, and prefrontal cortex and a down-regulation of DAT in the hypothalamus. Additionally, expression of both μ-opioid receptor (MOR) and preproenkephalin (PENK) was increased in nucleus accumbens, prefrontal cortex, and hypothalamus of mice from dams that consumed the HF diet. Epigenetic mechanisms have been associated with long-term programming of gene expression after various in utero insults. We observed global and gene-specific (DAT, MOR, and PENK) promoter DNA hypomethylation in the brains of offspring from dams that consumed the HF diet. These data demonstrate that maternal consumption of a HF diet can change the offsprings’ epigenetic marks (DNA hypomethylation) in association with long-term alterations in gene expression (dopamine and opioids) and behavior (preference for palatable foods).