ECE2017 Oral Communications Receptors & Signalling (5 abstracts)
AKR1C3-mediated adipose androgen generation drives lipotoxicity in polycystic ovary syndrome
Michael O’Reilly 1 , Punith Kempegowda 1 , Mark Walsh 3 , Angela Taylor 1 , Konstantinos Manolopoulos 1 , William Allwood 1 , Robert Semple 4 , Daniel Hebenstreit 3 , Warwick Dunn 1 , Jeremy Tomlinson 2 & Wiebke Arlt 1
1University of Birmingham, Birmingham, UK; 2University of Oxford, Oxford, UK; 3University of Warwick, Coventry, UK; 4University of Cambridge, Cambridge, UK.
Polycystic ovary syndrome (PCOS) is prevalent metabolic disorder in women, associated with androgen excess and insulin resistance. These two major features are closely correlated, but the direction of causality remains unclear. Aldoketoreductase type 1C3 (AKR1C3) converts the androgen precursor androstenendione to testosterone (T), and is highly expressed in subcutaneous (SC) adipose tissue. We hypothesised that adipose tissue represents an important site linking androgen activation and metabolic dysfunction in PCOS. We undertook metabolic phenotyping in 10 PCOS women and 10 age- and BMI-matched controls. Participants underwent an oral challenge with the androgen precursor DHEA, alongside adipose tissue microdialysis, with measurement of metabolic markers and adipose androgens in microdialysate fluid. Non-targeted serum metabolome analysis was performed before and after androgen exposure. SC adipose tissue biopsies were collected for RNA-sequencing. Complementary in vitro experiments in primary SC adipocytes and a preadipocyte cell line were performed to examine the effects of insulin and androgens on AKR1C3 expression and de novo lipogenesis, respectively. PCOS women had higher adipose T (P<0.0006) and dihydrotestosterone (DHT, P=0.01) than controls as measured by liquid chromatography-tandem mass spectrometry. Non-targeted serum metabolomics and adipose microdialysis revealed pro-lipogenic effects of androgens at baseline and after DHEA in PCOS. AKR1C3 mRNA expression was increased in PCOS SC adipose tissue (P=0.04). Transcriptional profiling revealed dysregulation of mitochondrial and inflammatory pathways in PCOS SC adipose tissue. In vitro studies showed that insulin upregulates adipose AKR1C3 expression and activity, and androgens enhance adipose de novo lipogenesis. Pharmacological inhibition of AKR1C3 decreased adipose tissue androgen generation and androgen-mediated de novo lipogenesis. Complementary in vivo and in vitro studies highlight that AKR1C3-mediated intra-adipose androgen activation drives lipotoxicity and adverse metabolic risk in PCOS, fuelling a vicious circle of androgen generation and insulin resistance. Selective inhibition of AKR1C3 holds promise as a novel therapeutic approach in PCOS.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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