Dataset Information

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.

SUBMITTER: Carbone L

PROVIDER: S-EPMC6917716 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Carbone Lucia L Davis Brett A BA Fei Suzanne S SS White Ashley A Nevonen Kimberly A KA Takahashi Diana D Vinson Amanda A True Cadence C Roberts Charles T CT Varlamov Oleg O

Scientific reports 20191217 1

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 mech ...[more]

PMID: 31848372

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Project description:ObjectiveTo identify novel transcriptomic changes to eutopic endometrium by exposure to chronic mild hypernadrogenemia (testosterone [T]) with/without exposure to an obesogenic Western-style diet (WSD).DesignTwo-by-two factorial arrangement of treatments.SettingNational primate research center.AnimalsRhesus macaque females were chronically exposed to T and/or consumed a WSD from menarche through adulthood. After 4.5 years of treatment, Tru-Cut endometrial biopsies were obtained at the midsecretory phase (n = 6-4/group), and paired-end sequencing of RNA was performed. Several females in the T, WSD, and T+WSD cohorts developed endometriosis within 6 months of biopsy; a separate analysis was performed contrasting diagnosis of endometriosis stage 0-2 versus stages 3 and 4 (American Society for Reproductive Medicine revised criteria).InterventionsChronic exposure to mild elevation of T (~five-fold elevation) and/or WSD from menarche until adulthood.Main outcome measuresLimma voom empirical Bayes pipeline was performed to detect differentially expressed RNAs (DEs) significantly impacted by treatments and endometriosis severity. Differentially expressed RNAs were then interrogated by Ingenuity Pathway Analyses and Protein Analysis through Evolutionary Relationships.ResultsTotal DEs included C versus T, 469; C versus WSD, 525; C versus T+WSD, 549; and T versus T+WSD, 1,505. The majority of DEs mapped to the ontology pathways: heterotrimeric G-protein signaling pathways Gi alpha and Gs alpha (C vs. T), WNT signaling (C vs. WSD and T vs. T+WSD), and Huntington disease (C vs. T+WSD). A total of 2,171 DEs from eutopic endometrium were altered by the presence of stage 3 and 4 endometriosis lesions.ConclusionsThe present global transcriptomic analyses demonstrate that the greatest magnitude of changes occurred in contrasts of C and T versus T+WSD, adding to the evidence that these two insults have a synergistic effect on female physiology. These data also support the concept that prior alterations to the function of eutopic endometrium increase the risk for endometriosis.

Project description:Study questionDoes developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone?Summary answerYoung female rhesus macaques treated for 3 years, beginning at menarche, with combined testosterone (T) and WSD have increased weight gain and insulin resistance compared to controls and animals treated with either T or WSD alone.What is known alreadyHyperandrogenemia is a well-established component of polycystic ovary syndrome (PCOS) and can be observed in peripubertal girls, indicating a potential pubertal onset of the disease. Obesity is often associated with hyperandrogenemia in peripubertal girls, and overweight girls appear to be at higher risk for the development of PCOS later in life.Study design, size, durationJuvenile (2.5- year old) female rhesus macaques were divided into four groups (n = 10/group): control animals receiving cholesterol implants and a control diet with 15% of calories derived from fat (C), animals receiving T implants (mean serum levels: 1.35 ± 0.01 ng/ml) and a control diet (T), animals receiving a cholesterol implant and a WSD with 36% of calories derived from fat (WSD) and animals receiving a T implant and a WSD (T + WSD). Animals were maintained on the treatments for 36 months and were 5.5 years old at study completion.Participants/materials, setting, methodsMetabolic testing consisted of body measurements including weight, dual-energy X-ray absorptiometry scans, activity monitoring, and glucose tolerance testing at zero months and at least once every 12 months for the remainder of the study. Indirect calorimetry and serum hormone assays were performed following 36 months of treatment.Main results and the role of chanceBody weight and fat mass gain were significantly increased in T + WSD at 24 and 36 months of treatment compared to the other three groups. Log transformed fasting insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were significantly increased in T + WSD animals at 3 years of treatment compared to all other groups. T-treatment caused a greater rate of decline in activity after 18 months, while food intake and metabolic rate were largely unaffected by treatments.Limitations reasons for cautionVariability was present in the metabolic parameters measured; however, this is similar to the heterogeneity observed in human populations.Wider implications of the findingsChronic hyperandrogenemia beginning at puberty may exacerbate metabolic dysfunction in women consuming a WSD and account for the increased rates of obesity and insulin resistance observed in PCOS patients. Counseling of female patient populations with elevated androgens about the potential benefit of consuming a lower fat diet could improve long-term metabolic health outcomes.Study funding/competing interest(s)Eunice Kennedy Shriver National Institute of Child Health & Human Development P50HD071836 and Oregon National Primate Center Grant P51 OD011092. The authors have no competing conflict of interests to disclose.

Dataset Information

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

Publications

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

Similar Datasets

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