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

BURGUEÑO A,; GONZALES MANSILLA, NOELIA L; SOOKOIAN S; PIROLA CJ

Cold Spring Harbor, New York

Simposio; 76th Symposium: Metabolism & Disease; 2011

Cold Spring Harbor Laboratory

Maternal environment during fetal life has a strong influence on modeling the metabolic profile of the progeny. We contrasted the hypothesis that maternal diet during pregnancy impacts on fetal metabolic programming through changes in liver mitochondrial DNA (mtDNA) content and transcriptional activity of Ppargc1a. We measured the liver mtDNA copy number in adult offspring of dams fed high fat diet (HFD) during gestation and lactation, and additionally examined the liver mRNA abundance of nuclear genes involved in the regulation of mtDNA transcription and replication, including Ppargc1a, a master transcriptional coactivator involved in the regulation of mitochondrial biogenesis. We also aimed to test whether the effect on fetal programming is sex-specific. Methods: Adult male and female offspring were fed either HFD or standard chow diet (SCD) for a 18–week period, generating 8 experimental groups. Results: Maternal HFD feeding during pregnancy is associated with a decreased liver mtDNA copy number (p<0.008). This effect was independent of the offspring sex or diet, and was significantly associated with fatty liver when dams were fed HFD (p<0.05, adjusted by HOMA-IR). We also found that maternal HFD feeding results in a male-specific significant reduction of the liver abundance of Ppargc1a mRNA (p<0.004), which significantly impacted on peripheral insulin resistance. Liver expression of Ppargc1a was inversely correlated with HOMA-IR (R= -0.53, p<0.0003). Only male offspring exposed to a chronic metabolic insult in adult life were insulin resistant, hyperleptinemic and showed abnormal liver and abdominal fat accumulation. Liver abundance of Tfam, Nrf1 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. This programming effect operates during adulthood and is hardly capable of being reversed as they strongly modify the organ performance and adaptation to metabolic challenges. Hence, early intervention during pregnancy is mandatory to reduce the alarming figures of prevalence of metabolic syndrome and associated conditions in children and adult population.