Intrauterine Fetal Growth Restriction and Sexually Dimorphic Programming of Adipocytes

Abstract

Worldwide, fetal growth restriction (FGR) affects 7 to 10% of pregnancies, or roughly 20.5 million infants each year. FGR not only increases neonatal mortality and morbidity but also the risk of obesity in later life. Currently, the molecular mechanisms by which FGR "programs" an obese phenotype are not well understood. Of note, studies demonstrate that FGR females are more prone to obesity as compared to males; however, the molecular mechanisms that lead to FGR are not known. Thus, I hypothesized that FGR causes sexually dimorphic programming of adipocytes by differentially regulating preadipocyte gene pathways. To test the hypothesis, we induced FGR using a sheep model subject to increased ambient hyperthermia. We collected perirenal adipose tissue from male and female near-term FGR and normal weight fetal lambs (N=4 in each group, 16 total). Second-generation RNA sequencing (RNAseq) was conducted on RNA isolated from adipose tissue to examine the differences in gene networks and pathways. For phenotypic results, averages across the four samples for each group were obtained. The current studies demonstrated that male FGR (MFGR) has a significantly greater mean fat globule area than normal-weight male fetus and a greater fat globule area than all other groups. In contrast, there was no significant difference in average fat globule area between female FGR (FFGR) and normal-weight female fetus. A four-way RNAseq comparison demonstrated significant differences in gene expression between FGR and control groups and between sexes. In conclusion, we observed a sexually dimorphic phenotype and gene pathways in response to FGR.