Exercise Prevents Maternal High-Fat Diet-Induced Hypermethylation of the Pgc-1a Gene and Age-Dependent Metabolic Dysfunction in the Offspring

Abnormal conditions during early development adversely affect later health. We investigated whether maternal exercise could protect offspring from adverse effects of a maternal high-fat diet (HFD) with a focus on the metabolic outcomes and epigenetic regulation of the metabolic master regulator, peroxisome proliferator-activated receptor coactivator-1 (Pgc-1). Female C57BL/6 mice were exposed to normal chow, an HFD, or an HFD with voluntary wheel exercise for 6 weeks before and throughout pregnancy. Methylation of the Pgc-1 promoter at CpG site -260 and expression of Pgc-1 mRNA were assessed in skeletal muscle from neonatal and 12-month-old offspring, and glucose and insulin tolerance tests were performed in the female offspring at 6, 9, and 12 months. Hypermethylation of the Pgc-1 promoter caused by a maternal HFD was detected at birth and was maintained until 12 months of age with a trend of reduced expression of Pgc-1 mRNA (P = 0.065) and its target genes. Maternal exercise prevented maternal HFD-induced Pgc-1 hypermethylation and enhanced Pgc-1 and its target gene expression, concurrent with amelioration of age-associated metabolic dysfunction at 9 months of age in the offspring. Therefore, maternal exercise is a powerful lifestyle intervention for preventing maternal HFD-induced epigenetic and metabolic dysregulation in the offspring.