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dc.contributor.authorO'Reilly, MWen
dc.contributor.authorKempegowda, Pen
dc.contributor.authorWalsh, Men
dc.contributor.authorTaylor, AEen
dc.contributor.authorManolopoulos, Ken
dc.contributor.authorAllwood, JWen
dc.contributor.authorSemple, Roberten
dc.contributor.authorHebenstreit, Den
dc.contributor.authorDunn, WBen
dc.contributor.authorTomlinson, JWen
dc.contributor.authorArlt, Wen
dc.date.accessioned2017-08-29T13:48:54Z
dc.date.available2017-08-29T13:48:54Z
dc.date.issued2017-09-01en
dc.identifier.issn0021-972X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266922
dc.description.abstractContext: 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 aldoketoreductase 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.
dc.description.sponsorshipThis work was funded by the Wellcome Trust (Clinical Research Training Fellowship 099909, to MOR, and Project Grant 092283, to WA), the BBSRC (BB/L006340/1, to DH) and the National Institute of Health Research (NIHR) UK.
dc.language.isoenen
dc.publisherOxford University Press
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleAKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndromeen
dc.typeArticle
prism.endingPage3339
prism.issueIdentifier9en
prism.publicationDate2017en
prism.publicationNameJournal of Clinical Endocrinology and Metabolismen
prism.startingPage3327
prism.volume102en
dc.identifier.doi10.17863/CAM.10381
dcterms.dateAccepted2017-06-09en
rioxxterms.versionofrecord10.1210/jc.2017-00947en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-09-01en
dc.contributor.orcidSemple, Robert [0000-0001-6539-3069]
dc.identifier.eissn1945-7197
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (098498/Z/12/Z)
cam.issuedOnline2017-06-22en
dc.identifier.urlhttps://academic.oup.com/jcem/article/102/9/3327/3868128en


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International