Synergistic Effects of Hyperandrogenemia and Obesogenic Western-style Diet on Transcription and DNA Methylation in Visceral Adipose Tissue of Nonhuman Primates

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.

Maternal Western-Style Diet Impairs Bone Marrow Development and Drives a Hyperinflammatory Phenotype in Hematopoietic Stem and Progenitor Cells in Fetal Rhesus Macaques

“…To address the impact of maternal obesity on FBM development and hematopoiesis, we studied two experimental groups of female rhesus macaques, including those that consumed either a low-fat control diet or those consuming a calorie-rich high-fat WSD for 3 years starting at 2.5 years of age (near menarche) ( Figure 1A ). Animals consuming the WSD were consistently heavier and exhibited significantly greater percentage total body fat than control animals, as previously reported (Carbone et al, 2019; Varlamov et al, 2017) ( Figures 1B and C ). At 5.5 years of age, animals underwent timed-mated breeding (Bishop et al, 2021).…”

Short-Term Caloric Restriction Attenuates Obesity-Induced Pro-inflammatory Response in Male Rhesus Macaques

“…In summary, the present study advances our understanding of the functional and transcriptional response in SC-WAT associated with dynamic changes in fat mass in response to diet-induced obesity and weight loss and expands our previous studies in NHPs [17,18,20,[64][65][66]. Our study has several limitations.…”

“…Consistent with this hypothesis, we recently conducted the whole-genome gene expression and epigenetic analysis in visceral WAT of female rhesus macaques exposed to a WSD and excess androgens in combination or individually. This study demonstrated that testosterone could modulate the effects of WSD on transcription of lipid metabolism genes and DNA methylation in females WAT [64].…”

Three-Dimensional Genome Interactions Identify Potential Adipocyte Metabolism-Associated Gene STON1 and Immune-Correlated Gene FSHR at the rs13405728 Locus in Polycystic Ovary Syndrome

“…Therefore. prenatally androgenized (PNA) models ( 39 ) or testosterone-treated models ( 20 ) were used as PCOS-like models for hyperandrogenism basis, which would highly increase the expression of AR ( 40 ). In our findings, AR was identified as the common TF of STON1 and FSHR and positively correlated with their expression in ovary tissues.…”