Maternal high-fat intake during pregnancy programs metabolic-syndrome-related phenotypes through liver mitochondrial DNA copy number and transcriptional activity of liver PPARGC1A.

UNLABELLED: In this study, we contrasted the hypothesis that maternal diet during pregnancy has an impact on fetal metabolic programming through changes in liver mitochondrial DNA (mtDNA) content and transcriptional activity of Ppargc1a and that these effects are sex specific. METHODS: Rats were fed either high-fat (HFD) or standard chow diet (SCD) during gestation and lactation. The resulting adult male and female offspring were fed either HFD or SCD for an 18-week period, generating eight experimental groups. RESULTS: Maternal HFD feeding during pregnancy is associated with a decreased liver mtDNA copy number (P<.008). This effect was independent of the offspring sex or diet, and was significantly associated with fatty liver when dams were fed HFD (P<.05, adjusted by homeostasis model assessment of insulin resistance, HOMA-IR). We also found that maternal HFD feeding results in a male-specific significant reduction of the liver abundance of Ppargc1a mRNA (P<.004), which significantly impacted peripheral insulin resistance. Liver expression of Ppargc1a was inversely correlated with HOMA-IR (R=-0.53, P<.0003). Only male offspring exposed to a chronic metabolic insult in adult life were insulin resistant and hyperleptinemic, and showed abnormal liver and abdominal fat accumulation. Liver abundance of Tfam, Nrf1, Hnf4a, Pepck and Ppparg mRNA was not associated with maternal programming. In conclusion, maternal high-fat diet feeding during pregnancy programs liver mtDNA content and the transcriptional activity of Ppargc1a, which strongly modulates, in a sex-specific manner, glucose homeostasis and organ fat accumulation in adult life after exposure to a nutritional insult.