CMKLR1 deficiency maintains ovarian steroid production in mice treated chronically with dihydrotestosterone

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.

Chicken Is a Useful Model to Investigate the Role of Adipokines in Metabolic and Reproductive Diseases

“…Chemerin expression is also increased in the ovaries of rats treated with 5alpha-dehydrotestosterone (DHT) (mimicking PCOS) that is associated with a decrease in oestradiol secretion in granulosa cells and induces apoptosis [ 210 ]. In mice with CMKLR1 gene deletions, the effects of chronic DHT treatment on ovarian function in experimental PCOS are largely reduced, suggesting a role of the chemerin system in PCOS pathology [ 211 ]. As already mentioned, PCOS syndrome is, in some cases, associated with insulin resistance, which can both be treated with antidiabetic drugs.…”

Deficiency of Gpr1 improves steroid hormone abnormality in hyperandrogenized mice

“…CMKLR1 is the most well-characterized Chemerin receptor, and most of the biological functions of Chemerin have been shown to depend on CMKLR1 activation [ 28 ]. Our recent study showed that CMKLR1 gene deletion attenuates the effects of chronic DHT treatment on ovarian function in experimental PCOS [ 29 ]. Although Chemerin is the only known ligand for GPR1, few functions have been suggested for GPR1.…”

Regulation of androgen receptor signaling by ubiquitination during folliculogenesis and its possible dysregulation in polycystic ovarian syndrome

“…Chronic and abnormally high androgen levels suppress antral follicular development 39 . It has been previously demonstrated that androgen resulted in suppressed antral follicular growth and estrogen secretion in the rats and mice 26 , 40 , 41 . In addition, testosterone or DHT supplementation in pig oocytes cultures medium significantly increased the proportion of oocytes arrested in the metaphase I stage 42 .…”