AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome

Michael O'reilly, Punith Kempegowda, Mark Walsh, Angela Taylor, Konstantinos Manolopoulos, J. William Allwood, Robert K Semple, Daniel Hebenstreit, Warwick Dunn, Jeremy Tomlinson, Wiebke Arlt

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)
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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 ten PCOS women, in comparison to ten 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, non-targeted serum metabolomics revealed pro-lipogenic effects of androgens in PCOS women only. In vitro studies showed that insulin increased adipose AKR1C3 expression and activity while androgen exposure increased adipocyte de novo lipid synthesis. Pharmacological AKR1C3 inhibition in vitro decreased de novo lipogenesis.
Conclusions
These findings define a novel intra-adipose mechanism of androgen activation that contributes to adipose remodelling and a systemic lipotoxic metabolome, with intra-adipose androgens driving lipid accumulation and insulin resistance in PCOS. AKR1C3 represents a promising novel therapeutic target in PCOS.
Original languageEnglish
Pages (from-to)3327–3339
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number9
Early online date22 Jun 2017
DOIs
Publication statusPublished - 1 Sept 2017

Keywords

  • adipose tissue
  • androgens
  • AKR1C3
  • polycystic ovary syndrome

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