Abstract
Elevated serum chemerin levels correlate with increased severity of polycystic ovary syndrome (PCOS). However, the role of CMKLR1 signaling in ovarian biology under conditions of excess DHT remains unclear. In this study we compared the effects of continuous 90-day high dose DHT exposure (83.3 □g/day) on wild type and CMKLR1-deficient mice. DHT induced PCOS-like clinical signs in wild type mice as well as significant changes in the expression of hormone receptors, steroid synthesis enzymes, and BMPs and their receptors. In contrast, CMKLR1-deficient mice significantly attenuated DHT-induced clinical signs of PCOS and alterations in ovarian gene expression. To determine whether the BMP4 signaling pathway was involved in the pathogenic effects of CMKLR1 signaling in DHT-induced ovarian steroidogenesis, antral follicles were isolated from wild type and CMKLR1 knockout (KO) mice and treated in vitro with combinations of hCG, DHT, and BMP4 inhibitors. BMP4 inhibition attenuated the induction effects of hCG and DHT on estrogen and progesterone secretion in CMKLR1 KO mice, but not in WT mice, implicating the BMP4 signaling pathway in the CMKLR1-dependent response to DHT. In conclusion, CMKLR1 gene deletion attenuates the effects of chronic DHT treatment on ovarian function in experimental PCOS, likely via BMP4 signaling.
Highlights
Elevated serum chemerin levels correlate with increased severity of polycystic ovary syndrome (PCOS)
PCOS is a common endocrine disorder characterized by reproductive, endocrine, and metabolic features, including anovulation, infertility, hyperandrogenism, obesity, hyperinsulinism, and an increased risk of type 2 diabetes and cardiovascular disease[22]
A chemoattractant ligand for CMKLR13,6, has been identified as a novel adipokine associated with obesity and metabolic syndrome and has been shown to promote adipogenesis and regulate glucose metabolism[3,4,7,8]
Summary
Elevated serum chemerin levels correlate with increased severity of polycystic ovary syndrome (PCOS). DHT induced PCOS-like clinical signs in wild type mice as well as significant changes in the expression of hormone receptors, steroid synthesis enzymes, and BMPs and their receptors. To determine whether the BMP4 signaling pathway was involved in the pathogenic effects of CMKLR1 signaling in DHT-induced ovarian steroidogenesis, antral follicles were isolated from wild type and CMKLR1 knockout (KO) mice and treated in vitro with combinations of hCG, DHT, and BMP4 inhibitors. CMKLR1 gene deletion attenuates the effects of chronic DHT treatment on ovarian function in experimental PCOS, likely via BMP4 signaling. In a rat model of PCOS, in which exposure to 5α -dihydrotestosterone (DHT)[12] recapitulates the reproductive and metabolic phenotypes of human PCOS12, DHT treatment resulted in increased expression of chemerin and CMKLR1 in antral follicles[13]. We used freshly isolated ovarian antrals from wild type and CMKLR1 KO mice to explore the intersecting molecular signaling pathways activated by hyperandrogenic stimulation
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