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Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone.

ABSTRACT: Does developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone?Young 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.Hyperandrogenemia 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.Juvenile (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.Metabolic 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.Body 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.Variability was present in the metabolic parameters measured; however, this is similar to the heterogeneity observed in human populations.Chronic 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.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.

SUBMITTER: True CA

PROVIDER: S-EPMC5850848 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone.

True C A CA Takahashi D L DL Burns S E SE Mishler E C EC Bond K R KR Wilcox M C MC Calhoun A R AR Bader L A LA Dean T A TA Ryan N D ND Slayden O D OD Cameron J L JL Stouffer R L RL

Human reproduction (Oxford, England) 20170901 9

<h4>Study question</h4>Does developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone?<h4>Summary answer</h4>Young 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.<h4>What is known already</h4>Hyperandrogenemia is a well-es ...[more]

PMID: 28854721

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Project description:Study questionWhat is the impact of prolonged exposure to hyperandrogenemia (T), Western-style diet (WSD) and the combination on metabolic and reproductive function in female rhesus macaques, particularly in the post-partum period?Summary answerCombined T + WSD worsened measures of insulin sensitivity and parameters of cyclicity following prolonged (5 years) exposure, but there was no effect on post-partum metabolic function.What is known alreadyWomen with hyperandrogenemia due to polycystic ovary syndrome are at higher risk for gestational diabetes and Type 2 diabetes post-partum, but it is unknown if this is related to hyperandrogenemia. Hyperandrogenemia in the presence of a WSD worsens metabolic function in female nonhuman primates.Study design, size, durationFemale rhesus macaques began treatment near menarche (roughly 2.5 years of age) consisting of either cholesterol (control; C) or testosterone (T) implants (average serum levels 1.4 ng/ml) and exposure to standard monkey chow or a WSD (15 vs 36% of calories from fat, respectively). The four groups were maintained on treatment for 3 years, underwent a fertility trial in Year 4 and continued with treatments through Year 5.Participants/materials, setting, methodsMetabolic measurements (glucose tolerance tests and double X-ray absorptiometry scans) were performed yearly, and results from 5 years of treatment are reported for all animals. Animals were bled daily for 30 days at 5 years to capture changes in ovarian cycle hormones, and ultrasound measurements were performed during the early follicular and luteal phase.Main results and the role of chanceAfter 5 years of treatment, WSD exposure moderately increased body weight and body fat, although control animals also had a high body mass index due to ad libitum feeding. Animals in the T + WSD group had increased fasting insulin and insulin secretion during an intravenous glucose tolerance test. WSD exposure also altered ovarian cycles, delaying the time to the E2 surge, decreasing progesterone and anti-Müllerian hormone levels and increasing the number of antral follicles present by ultrasound. Longitudinal assessment of metabolic function for only those animals that became pregnant in Year 4 of treatment revealed no differences in post-partum metabolism between groups, although WSD resulted in overall elevated weights, body fat and measures of insulin resistance.Large scale dataNone.Limitations, reasons for cautionThe small sample size and heterogeneity in metabolic effects observed in the T + WSD group are limitations of the current study, with only a subset of animals in this group showing impaired insulin resistance relative to controls. In addition, obesity in the C group prevented comparisons to lean animals.Wider implications of the findingsHyperandrogenemia combined with WSD had a greater impact on insulin sensitivity and ovarian function than either treatment alone.Study funding/competing interest(s)This work was supported by NIH grant P50 HD071836 to C.T.R., J.H. and C.T. and P51 OD011092 for support of the Oregon National Primate Research Center. All authors declare no competing interests.

Project description:BACKGROUND:Western diets are associated with increased incidences of obesity, hypertension, diabetes, and hypercholesterolemia, whereas Mediterranean diets, richer in polyphenols, monounsaturated fats, fruits, vegetables, poultry, and fish, appear to have cardiometabolic health benefits. Previous work has included population-based studies with limited evidence for causation or animal studies focused on single macro- or micronutrients; therefore, primate animal models provide an opportunity to determine potential mechanisms underlying the effects of dietary patterns on health and disease. OBJECTIVE:The aim of this study was to determine the effects of whole dietary patterns, either a Western or Mediterranean diet, on skeletal muscle mitochondrial bioenergetics in cynomolgus macaques. METHODS:In this study, 22 adult female cynomolgus macaques (∼11-14 y by dentition) were fed either a Western or Mediterranean diet for 30 mo. The Western diet was designed to mimic the diet of a middle-aged American woman and the Mediterranean diet included key aspects of Mediterranean diets studied in humans, such as plant-based proteins and fat, complex carbohydrates, and fiber. Diets were matched on macronutrient composition (16% protein, 54% carbohydrate, and 31% fat) and cholesterol content. Skeletal muscle was collected for high-resolution respirometry, citrate synthase activity, and western blot measurements. Pearson correlation analysis between respirometry measures and measures of carbohydrate metabolism was also performed. RESULTS:We found that consumption of a Western diet resulted in significantly higher mitochondrial respiration with fatty acid oxidation (FAO) (53%), FAO + complex I (52%), complex I + II (31%), max electron transport system (ETS) (31%), and ETS rotenone sensitive (31%) than did consumption of a Mediterranean diet. In addition, measures of respiration in response to fatty acids were significantly and positively correlated with both insulin resistance and plasma insulin concentrations. CONCLUSIONS:This study highlights the importance of dietary composition in mitochondrial bioenergetics and that diet can influence skeletal muscle mitochondrial respiration independently of other factors such as macronutrient composition.

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Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone.

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Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone.

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