Intrauterine growth restriction and docosahexanoic acid supplementation alter DNA methylation of the peroxisome proliferator activated receptor gamma promoter 2 in rat visceral adipose tissue.

摘要

Intrauterine growth restriction (IUGR) increases the risk for visceral obesity and metabolic complications, with males more affected. We have shown that IUGR increases visceral adipose tissue (VAT) and mRNA levels of the pro-adipogenic transcription factor, PPARγ2, in adolescent male rats but not females. Increased PPARγ2 expression may be influenced by epigenetics. Epigenetic modifications include DNA methylation, with decreased methylation commonly associated with increased expression. PPARγ2 expression is also affected by the presence its endogenous ligand, docosahexaenoic acid (DHA). We have shown that maternal DHA supplementation normalizes PPARγ2 mRNA in male rats.;The effect of IUGR and maternal DHA supplementation on DNA methylation of PPARγ2 is unknown. We hypothesize that IUGR will decrease DNA methylation of PPARγ2 P2 in males and maternal DHA supplementation will correct these changes. We further hypothesize that neither IUGR nor maternal DHA supplementation will alter DNA methylation of PPARγ2 P2 in females or of PPARγ2 P1 in males and females.;IUGR was induced by bilateral uterine artery ligation on day E19.5 of gestation. Maternal rats were fed a regular diet or diet containing 0.1% DHA. VAT was harvested at day 21 of life (d21) from control, IUGR, DHA, and IUGR+DHA male and female rats. PPARγ2 mRNA levels were analyzed using RT-PCR. Nucleotide specific DNA methylation of 21 sites within PPARγ2 P1 and 5 sites within P2 were analyzed using bisulfite modification.;IUGR increased methylation of PPARγ2 P2 in females (37.93±12.5%) compared to controls (19.72±8.7%)*. DHA control males had decreased methylation of P2 (4.95±0.1%) when compared to regular diet controls (10.61±5.0%)*. IUGR+DHA decreased methylation of P2 in males (20.2±3.1%) compared to DHA controls (33.6±4.7%)*. Neither IUGR nor DHA supplementation altered methylation of PPARγ2 P1 in males or females. *p≤0.05.;We conclude that changes in PPARγ2 promoter DNA methylatiγon in rat VAT at d21 do not reflect changes in PPARγ2 mRNA induced by IUGR or DHA. Additionally, DHA alone decreases methylation of P2 in males but not females, exerting a sex-specific effect. We speculate that IUGR and DHA-induced changes in PPARγ2 mRNA seen in male rat VAT may be due to other epigenetic changes, such as histone modifications.