| Description |
Intrauterine growth restriction (IUGR) predisposes individuals to adult diseases, including obesity. Although IUGR infants are born smaller than their appropriately grown counterparts, fat deposition in IUGR children is accelerated throughout childhood. Storage of excess lipid in the subcutaneous adipose tissue (SAT) protects against ectopic fat deposition in the liver, muscle, and visceral adipose tissue (1). However, if SAT becomes dysfunctional, as evidenced by an increase in the release of pro-inflammatory cytokines as well as activation of the unfolded protein response (UPR), visceral adipose tissue (VAT) is preferentially deposited. Fat deposition in IUGR children favors the formation of VAT over SAT. Failure of SAT to adequately expand in IUGR individuals suggests dysfunction in the SAT depot. Our group previously demonstrated that IUGR induces SAT dysfunction in male, but not female, weanling rat pups. Early onset adaptations of specific genes regulating SAT, including PPARγ2, may be altered in response to an unfavorable in utero environment. In 3T3L1 cell culture, a positive feedback loop has been proposed in which PPARγ2 activates the transcription of the Setd8 gene. Setd8, a lysine methyltransferase, monomethylates H4K20, which further increases transcription of PPARγ2 and PPARγ2 target genes. However, the presence of this feedback loop in vivo in adipose tissue remains unknown. Furthermore, sex differences in basal levels of PPARγ2-Setd8- 5 H4K20Me in male and female control rat pups and the effect of IUGR on the PPARγ2- Setd8-H4K20Me feedback loop are unknown. We hypothesized that basal regulation of the PPARγ2-Setd8-H4K20Me loop would be different between male and female control rat pups. We also hypothesized IUGR would alter the PPARγ2-Setd8-H4K20Me positive feedback loop in male, but not female, d21 SAT prior to the onset of obesity. To test this hypothesis, we used a well-characterized rat model of uteroplacental insufficiency-induced IUGR. Our study demonstrated that sex differences exist between basal levels of PPARγ2-Setd8-H4K20Me in male and female control rat pups. Our results also demonstrated that IUGR dysregulates the PPARγ2-Setd8-H4K20Me positive feedback loop in a sex-specific manner, with the majority of molecular effects confined to male rat pups. Our sex-specific molecular observations may partially explain the varying responses of male and female adipose tissue to IUGR. |
