Journal article
AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome
- 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.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.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.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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Version of record, pdf, 1.4MB, Terms of use)
-
- Publisher copy:
- 10.1210/jc.2017-00947
Authors
+ National Institutes of
Health Research
More from this funder
- Grant:
- NIHR Biomedical Research Center Oxford to J.W.T
+ Biotechnology and Biological Sciences Research
Council
More from this funder
- Grant:
- BB/L006340/1 to D.H
- Publisher:
- Oxford University Press
- Journal:
- Journal of Clinical Endocrinology and Metabolism More from this journal
- Volume:
- 102
- Issue:
- 9
- Pages:
- 3327–3339
- Publication date:
- 2017-06-22
- Acceptance date:
- 2017-06-09
- DOI:
- EISSN:
-
1945-7197
- ISSN:
-
0021-972X
- Pmid:
-
28645211
- Language:
-
English
- Pubs id:
-
pubs:702445
- UUID:
-
uuid:88aec93d-98ef-4135-81ed-0f4818bb3c8b
- Local pid:
-
pubs:702445
- Source identifiers:
-
702445
- Deposit date:
-
2017-09-15
- ARK identifier:
Terms of use
- Copyright holder:
- O’Reilly et al
- Copyright date:
- 2017
- Notes:
- This article has been published under the terms of the Creative Commons Attribution License (CC BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the authors.
- Licence:
- CC Attribution (CC BY)
If you are the owner of this record, you can report an update to it here: Report update to this record