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AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome
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O’Reilly, Michael W., Kempegowda, Punith, Walsh, Mark David, Taylor, Angela E., Manolopoulos, Konstantinos N., Allwood, J. William, Semple, Robert K., Hebenstreit, Daniel, Dunn, Warwick B., Tomlinson, Jeremy W. and Arlt, Wiebke (2017) AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism, 102 (9). pp. 3327-3339. doi:10.1210/jc.2017-00947
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Official URL: http://dx.doi.org/10.1210/jc.2017-00947
Abstract
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.
| Item Type: | Journal Article | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Subjects: | R Medicine > RG Gynecology and obstetrics | ||||||||
| Divisions: | Faculty of Science > Life Sciences (2010- ) | ||||||||
| Library of Congress Subject Headings (LCSH): | Polycystic ovary syndrome , Adipose tissues | ||||||||
| Journal or Publication Title: | The Journal of Clinical Endocrinology & Metabolism | ||||||||
| Publisher: | The Endocrine Society | ||||||||
| ISSN: | 0021-972X | ||||||||
| Official Date: | 1 September 2017 | ||||||||
| Dates: |
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| Volume: | 102 | ||||||||
| Number: | 9 | ||||||||
| Page Range: | pp. 3327-3339 | ||||||||
| DOI: | 10.1210/jc.2017-00947 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||
| Funder: | Wellcome Trust (London, England), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), National Institute for Health Research (Great Britain) (NIHR) | ||||||||
| Grant number: | Clinical Research Training Fellowship 099909, Project Grant 092283 Wellcome Trust (London, England), BB/L006340/1 (BBSRC) |
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