Hyperandrogenemia and western-style diet act synergistically on transcription and DNA methylation in visceral adipose tissue of a non-human primate model [RRBS]

We have recently developed a nonhuman primate (NHP) model to address the effects of hyperandrogenemia (modestly elevated testosterone; T), a high-fat, obesogenic Western-style diet (WSD), or combined T+WSD. To address the molecular mechanisms underlying adipocyte dysfunction, visceral adipose tissue biopsies were analyzed for whole-genome gene expression and DNA methylation, using RNA-seq and reduced-representation bisulfite sequencing (RRBS), respectively. We show that the combination of T + WSD induces a significantly stronger transcriptional response than T or WSD alone, including regulation of genes whose expression is altered in adipose tissue of PCOS women. Gene expression patterns indicate alterations in cAMP, LXR/RXR, HIPPO, Wnt signaling and eicosanoid and retinol biosynthesis pathways. Analysis of DNA methylation shows that genes from the cAMP signaling pathway are also differentially methylated in T +WSD, which also globally resulted in a greater number of differentially methylated regions (DMRs) than T or WSD alone. Collectively, our results show that hyperandrogenemia and WSD exhibit synergistic effects on the visceral adipose tissue transcriptome and methylome, resulting in activation of biological processes that may contribute to the adipose tissue dysfunction characteristic of PCOS. White Adipose Tissue biopsies from four experimental groups of rhesus macaques (control, testosterone, western style diet, and testosterone + western style diet) of 6 replicates per group, subjected to whole transcriptome analysis and reduced representation bisulfite sequencing.