Abstract
Context:Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder occurring in up to 10% of women of reproductive age. PCOS is associated with insulin resistance and cardiovascular risk. Androgen excess is a defining feature of PCOS and has been suggested as causally associated with insulin resistance; however, mechanistic evidence linking both is lacking. We hypothesized that adipose tissue is an important site linking androgen activation and metabolic dysfunction in PCOS.Methods:We performed a human deep metabolic in vivo phenotyping study examining the systemic and intra-adipose effects of acute and chronic androgen exposure in 10 PCOS women, in comparison with 10 body mass index–matched healthy controls, complemented by in vitro experiments.Results:PCOS women had increased intra-adipose concentrations of testosterone (P = 0.0006) and dihydrotestosterone (P = 0.01), with increased expression of the androgen-activating enzyme aldo-ketoreductase type 1 C3 (AKR1C3) (P = 0.04) in subcutaneous adipose tissue. Adipose glycerol levels in subcutaneous adipose tissue microdialysate supported in vivo suppression of lipolysis after acute androgen exposure in PCOS (P = 0.04). Mirroring this, nontargeted serum metabolomics revealed prolipogenic effects of androgens in PCOS women only. In vitro studies showed that insulin increased adipose AKR1C3 expression and activity, whereas androgen exposure increased adipocyte de novo lipid synthesis. Pharmacologic AKR1C3 inhibition in vitro decreased de novo lipogenesis.Conclusions:These findings define an intra-adipose mechanism of androgen activation that contributes to adipose remodeling and a systemic lipotoxic metabolome, with intra-adipose androgens driving lipid accumulation and insulin resistance in PCOS. AKR1C3 represents a promising therapeutic target in PCOS.
Highlights
Baseline circulating androgens, measured by LC-MS/ MS, were all significantly higher in Polycystic ovary syndrome (PCOS) than in controls, as was insulin resistance assessed by Homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.003) (Supplemental Table 1)
Truncal fat mass and volume on body composition imaging by dual x-ray absorptiometry were increased in the PCOS group compared with matched controls (Supplemental Table 1)
These findings demonstrate the expected systemic androgen excess (AE), insulin resistance, and increased visceral adiposity in PCOS subjects in comparison with sex, age, and BMImatched controls
Summary
We performed a human deep metabolic in vivo phenotyping study examining the systemic and intra-adipose effects of acute and chronic androgen exposure in 10 PCOS women, in comparison with 10 body mass index–matched healthy controls, complemented by in vitro experiments. Study participants Women with PCOS aged between 18 and 40 years were recruited from outpatient clinics at University Hospitals Birmingham and Birmingham Women’s Hospital. PCOS was diagnosed according to the Rotterdam European Society of Human Reproduction and Embryology 2004 criteria, with the presence of two or more of the following: oligo/anovulation (Anov), clinical signs of AE, and polycystic ovaries (PCOs) on ultrasound [10]; only PCOS women with clinical or biochemical signs of AE were recruited to the in vivo study (phenotypes AE + Anov + PCO, AE + Anov, and AE + PCO). All healthy controls were age- and BMI-matched, and recruited via local advertisement, with exclusion of PCOS on clinical and biochemical grounds. Excised adipose tissue was immediately placed in RNALater (Life Technologies, Paisley, United Kingdom) and stored at 220°C for subsequent RNA extraction
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