The role of GPR1 signaling in mice corpus luteum

Abstract

Chemerin, a chemokine, plays important roles in immune responses, inflammation, adipogenesis, and carbohydrate metabolism. Our recent research has shown that chemerin has an inhibitory effect on hormone secretion from the testis and ovary. However, whether G protein-coupled receptor 1 (GPR1), the active receptor for chemerin, regulates steroidogenesis and luteolysis in the corpus luteum is still unknown. In this study, we established a pregnant mare serum gonadotropin-human chorionic gonadotropin (PMSG-hCG) superovulation model, a prostaglandin F2α (PGF2α) luteolysis model, and follicle and corpus luteum culture models to analyze the role of chemerin signaling through GPR1 in the synthesis and secretion of gonadal hormones during follicular/luteal development and luteolysis. Our results, for the first time, show that chemerin and GPR1 are both differentially expressed in the ovary over the course of the estrous cycle, with highest levels in estrus and metestrus. GPR1 has been localized to granulosa cells, cumulus cells, and the corpus luteum by immunohistochemistry (IHC). In vitro, we found that chemerin suppresses hCG-induced progesterone production in cultured follicle and corpus luteum and that this effect is attenuated significantly by anti-GPR1 MAB treatment. Furthermore, when the phosphoinositide 3-kinase (PI3K) pathway was blocked, the attenuating effect of GPR1 MAB was abrogated. Interestingly, PGF2α induces luteolysis through activation of caspase-3, leading to a reduction in progesterone secretion. Treatment with GPR1 MAB blocked the PGF2α effect on caspase-3 expression and progesterone secretion. This study indicates that chemerin/GPR1 signaling directly or indirectly regulates progesterone synthesis and secretion during the processes of follicular development, corpus luteum formation, and PGF2α-induced luteolysis.

Deficiency of Gpr1 improves steroid hormone abnormality in hyperandrogenized mice

“…It has been reported that GPR1 is expressed in metabolically active tissues and plays a functional role in glucose homoeostasis in obesity [ 30 ]. A new study from our lab shows that Chemerin and GPR1 are expressed in the mouse ovary during the estrous cycle and that Chemerin/GPR1 signaling could suppress hCG-induced progesterone synthesis and secretion during follicle development, partly through PI3K [ 31 ].…”

Identification of Three Novel Splicing Variants and Expression Analysis of Chicken GPR1 Gene

“…Goralski et al study suggested that chemerin and CMKLR1 could regulate adipogenesis and adipocyte metabolism through ERK1/2 signaling pathway [ 54 ]. Various follicle classes have different lipid characteristics [ 55 ]; by adding GPR1 antibody and PI3K signaling inhibitor we find that the chemerin/GPR1 and PI3K signaling pathways may be involved in follicular development [ 56 ]. Therefore, GPR1 is the only known receptor for chemerin which also may regulate the follicular development through regulating follicular lipid accumulation.…”

International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin1) and GPR1 (Chemerin2) Nomenclature, Pharmacology, and Function

“…In contrast to CMKLR1, GPR1 was predominately expressed in the stromal vascular fraction of white adipose tissue, not the adipocytes ( Rourke et al, 2014 ). GPR1 mRNA was also detected in the ovaries, more precisely with high protein expression in the oocytes of developing follicles, and in the thecal cells, granulosa cells, luteal cells, and interstitial cells of the stroma ( Yang et al, 2016 ).…”

“…In mice, similar to that found in humans, chemerin mRNA was detected in a wide range of different tissues. The highest expression was seen in liver, skin, white adipose tissue, and placenta ( Goralski et al, 2007 ; Banas et al, 2015 ), but chemerin mRNA was also present in ovary, skin, lung, liver, ilieum, colon, testis, thymus, spleen, mesenteric lymph nodes, and Peyer’s patches ( Luangsay et al, 2009 ; Yang et al, 2016 ). Chemerin mRNA levels were significantly higher in white adipose tissue compared with brown, and they were more abundant in adipocytes than in the stromal vascular fraction of white adipose tissue, a similar expression pattern to its receptor CMKLR1 ( Goralski et al, 2007 ).…”

“…Most recently, a novel role of GPR1 was reported in progesterone synthesis in mice. Chemerin suppressed progesterone production in cultured follicle and corpus luteum and prostaglandin F2 α -activated caspase-3, resulting in a subsequent reduction in progesterone secretion, both of which were mediated by this receptor ( Yang et al, 2016 ). Likewise, although the receptor(s) responsible has yet to be identified, chemerin inhibited production of progesterone and estrodial in human ( Reverchon et al, 2012 ) and rat ( Wang et al, 2012 ) granulosa cells and testosterone in rat testis ( Li et al, 2014b ), suggesting a role for chemerin in the regulation of gonodal steriogenesis.…”