Abstract
Polycystic ovary syndrome (PCOS) is a major reproductive disorder that is responsible for 80% of anovulatory infertility and that is associated with hyperandrogenemia, increased risk of obesity, and white adipose tissue (WAT) dysfunction. We have previously demonstrated that the combination of chronic testosterone (T) treatment and an obesogenic Western-style diet (WSD) exerts synergistic functional effects on WAT, leading to increased lipid accumulation in visceral adipocytes by an unknown mechanism. In this study, we examined the whole-genome transcriptional response in visceral WAT to T and WSD, alone and in combination. We observed a synergistic effect of T and WSD on gene expression, resulting in upregulation of lipid storage genes concomitant with adipocyte hypertrophy. Because DNA methylation is known to be associated with body fat distribution and the etiology of PCOS, we conducted whole-genome DNA methylation analysis of visceral WAT. While only a fraction of differentially expressed genes also exhibited differential DNA methylation, in silico analysis showed that differentially methylated regions were enriched in transcription factor binding motifs, suggesting a potential gene regulatory role for these regions. In summary, this study demonstrates that hyperandrogenemia alone does not induce global transcriptional and epigenetic response in young female macaques unless combined with an obesogenic diet.
Highlights
Animal studies have shown that prenatal programing by maternal androgens predisposes offspring to increased adiposity and other metabolic features of Polycystic ovary syndrome (PCOS), as demonstrated in nonhuman primate (NHP)[23,24], sheep[25,26], and rodent[27,28] models of PCOS
We demonstrate that, similar to the effects of T and Western-style diet (WSD) on systemic metabolic and white adipose tissue (WAT)-specific parameters described in our previous studies[35,36], the combination of hyperandrogenemia and WSD induced synergistic effects on both gene expression and DNA methylation in visceral WAT of rhesus macaques
We describe the relationship between differential transcription, DNA methylation, and adipocyte size, and provide in silico analysis, suggesting that T + WSD– induced differential methylation may affect transcription factor (TF) binding sites that are computationally predicted to act as the trans-regulatory elements
Summary
Animal studies have shown that prenatal programing by maternal androgens predisposes offspring to increased adiposity and other metabolic features of PCOS, as demonstrated in nonhuman primate (NHP)[23,24], sheep[25,26], and rodent[27,28] models of PCOS. All experimental animals in this study experienced ovulatory menstrual cycles to some extent; mild hyperandrogenemia alone and in combination with a WSD impaired several markers of normal ovarian and uterine function[37,38], which resulted in increased time to pregnancy (T and T + WSD groups), reduced pregnancy rates (WSD and T + WSD groups), and increased early pregnancy loss[39] These studies suggest a synergistic effect of T and WSD treatment on many metabolic and reproductive outcomes. We demonstrate that, similar to the effects of T and WSD on systemic metabolic and WAT-specific parameters described in our previous studies[35,36], the combination of hyperandrogenemia and WSD induced synergistic effects on both gene expression and DNA methylation in visceral WAT of rhesus macaques. We describe the relationship between differential transcription, DNA methylation, and adipocyte size, and provide in silico analysis, suggesting that T + WSD– induced differential methylation may affect transcription factor (TF) binding sites that are computationally predicted to act as the trans-regulatory elements
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