Deficiency of Gpr1 improves steroid hormone abnormality in hyperandrogenized mice

Abstract

BackgroundPolycystic ovary syndrome (PCOS) is a complex genetic disease with multifarious phenotypes. Many researches use dehydroepiandrosterone (DHEA) to induce PCOS in pubertal mouse models. The aim of this study was to investigate the role of GPR1 in dehydroepiandrosterone (DHEA)-induced hyperandrogenized mice.MethodsPrepubertal C57BL/6 mice (25 days of age) and Gpr1-deficient mice were each divided into two groups and injected daily with sesame oil with or without DHEA (6 mg/100 g) for 21 consecutive days. Hematoxylin and eosin (H&E) staining was performed to determine the characteristics of the DHEA-treated ovaries. Real-time PCR was used to examine steroid synthesis enzymes gene expression. Granulosa cell was cultured to explore the mechanism of DHEA-induced, GPR1–mediated estradiol secretion.ResultsDHEA treatment induced some aspects of PCOS in wild-type mice, such as increased body weight, elevated serum testosterone, increased number of small, cystic, atretic follicles, and absence of corpus luteum in ovaries. However, Gpr1 deficiency significantly attenuated the DHEA-induced weight gain and ovarian phenotype, improving steroidogenesis in ovaries and estradiol synthesis in cultured granulosa cells, partially through mTOR signaling.ConclusionsIn conclusion, Gpr1 deficiency leads to the improvement of steroid synthesis in mice hyperandrogenized with DHEA, indicating that GPR1 may be a therapeutic target for DHEA-induced hyperandrogenism.Electronic supplementary materialThe online version of this article (10.1186/s12958-018-0363-9) contains supplementary material, which is available to authorized users.

Short‐term rapamycin administration elevated testosterone levels and exacerbated reproductive disorder in dehydroepiandrosterone‐induced polycystic ovary syndrome mice

“…To explain this phenomenon, mRNA expression of genes involved in steroidogenesis was explored. Consistent with previous results, DHEA exposure decreased Cyp11a1 , Hsd3b , and Cyp17a1 expression, which was likely due to negative feedback of DHEA, but increased Cyp19a1 expression, which converts excess DHEA into estrogens [ 22 , 23 ]. Treatment with rapamycin further reduced Cyp11a1 , Cyp17a1 , and Cyp19a1 expression, probably because cyclic adenosine monophosphate response element-binding protein, downstream of S6K1, could be significantly decreased by rapamycin and mediates changes in gene expression [ 9 , 10 ].…”

Chemerin: A Functional Adipokine in Reproductive Health and Diseases

“…Additionally, recombinant chemerin (r-chemerin) influenced both basal, GnRH- and/or insulin-mediated LH and FSH in porcine primary anterior pituitary cells [ 44 ]. In female mice, deficiency of Gpr1 leads to lower mRNA values of GnRH in the hypothalamus, and higher mRNA values of FSH in the pituitary glands, along with higher serum E 2 levels relative to the wild type [ 46 ]. However, deficiency of Cmklr1 does not affect the serum LH, FSH, estradiol (E 2 ), and progesterone (P 4 ) levels in female mice [ 47 ].…”

“…Moreover, Cmklr1 deficiency partially alleviated the ovarian functions (ovary morphology and steroidogenesis) and lipid accumulation caused by DHT treatment in female mice [ 47 , 103 ]. Gpr1 deficiency also alleviated the DHEA-induced weight gain and ovarian morphological changes, improved the expression of steroid enzymes in ovaries, and E 2 synthesis in cultured granulosa cells, and these effects were partially through the mTOR signaling pathway [ 46 ]. More importantly, specific nanobody targeting CMKLR1 abolished chemerin-induced P 4 inhibition in human luteinized granulosa cells [ 89 ], and antibodies targeting GPR1 attenuated DHEA-induced E 2 in mouse ovarian granulosa cells [ 46 ].…”

“…Gpr1 deficiency also alleviated the DHEA-induced weight gain and ovarian morphological changes, improved the expression of steroid enzymes in ovaries, and E 2 synthesis in cultured granulosa cells, and these effects were partially through the mTOR signaling pathway [ 46 ]. More importantly, specific nanobody targeting CMKLR1 abolished chemerin-induced P 4 inhibition in human luteinized granulosa cells [ 89 ], and antibodies targeting GPR1 attenuated DHEA-induced E 2 in mouse ovarian granulosa cells [ 46 ]. These studies demonstrate that the chemerin system participates in the pathogenesis of PCOS, and targeting the receptors provides a promising therapeutic strategy.…”

Glucagon-like peptide-1 receptor agonists decrease hyperinsulinemia and hyperandrogenemia in dehydroepiandrosterone-induced polycystic ovary syndrome mice and are associated with mitigating inflammation and inducing browning of white adipose tissue

“…The ovary is one of the primary sites of androgen synthesis in women. Numerous steroid hormone synthesis-related enzymes, including steroidogenic acute regulatory protein (STAR), steroid 17 alpha-hydroxylase/17,20 lyase (CYP17A1), 3 beta-hydroxysteroid dehydrogenase (3β-HSD), and cytochrome P450 family 19 subfamily A member 1 (CYP19A1), are present [ 4 ]. For example, CYP17A1, a crucial enzyme in androgen production, is considerably increased in PCOS mice [ 5 ].…”