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  • In the present study we found that the expression

    2022-01-18

    In the present study, we found that the expression of GPR120 in decidua from women of spontaneous abortion was significantly downregulated compared to the decidua from that of normal pregnancy. Moreover, GPR120 deletion (GPR120−/−) or inhibition predisposed mice to LPS or RU486 induced abortion, indicating that it may play a role in decidualization and the maintenance of pregnancy. Further experiments showed that GPR120 activation could promote decidualization by upregulating glucose transporter-1 (GLUT1) mediated glucose uptake and glucose-6-phophate dehydrogenase (G6PD) mediated pentose-phosphate pathway (PPP). FOXO1 was upregulated by GPR120 via ERK1/2 and AMPK signaling and was responsible for the upregulation of GLUT1. Besides, activation of GPR120 was found to upregulate CXCL12, TGFβ and IL-15 expression from DSCs, chemokine and cytokines dominant in dNK cell recruitment and education. Finally, we found that activation of GPR120 could ameliorate LPS induced abortion in the mice. Altogether, our results indicate that GPR120 plays protective role in maintaining pregnancy and reduces the incidence of spontaneous abortion by promoting decidualization during early pregnancy and, therefore, represents a potential target for diagnosis and treatment of RSA.
    Materials and methods
    Results
    Discussion G-protein-coupled receptors (GPCRs) which are charaterized by a common motif with seven transmembrane domains constitute the largest membrane protein receptor family in mammals by far [14,22]. In recent years, some of the GPCRs are identified as fatty CVT-313 mg receptors, such as GPR40, GPR41, GPR84 and GPR120 [[23], [24], [25]]. GPR120, the receptor for ω-3 PUFAs, is reported to be involved in the regulation of various cellular and physiological functions. There are several lines of evidence suggest that GPR120 may play significant role in the maintenance of pregancy. Firstly, ω-3 PUFAs such as DHA and EPA, the ligands of GPR120, are the acknowledged nutritional addition during pregnancy [26,27]. Human clinical trials and studies with animal models have suggested that supplementation of ω-3 PUFAs during pregnancy can maintain gestation length and fetal growth, prevent preterm birth and decrease the rate of gestational diabetes [28]. ω-3 PUFAs are known to contribute to the maintenance of the immune defense system by promoting the differentiation of T cells to a Th2 phenotype in pregnancy and by shifting the Th1/Th2 ratio from a deleterious proinflammatory Th1 phenotype to a protective anti-inflammatory Th2 phenotype [9,29], indicative of their role in the regulation of maternal-fetal immune microenvironment. Secondly, GPR120 has been detected in human placenta [15]. As a multifunctional molecule, GPR120 is critical in the regulation of glucose metabolism [30]. Interestingly, the accummulated glycogen in DSCs demonstrated that upregulated glucose metabolism is indispensable for energy supply and biosynthesis during decidualization. Therefore, it is resonable to hypothesize that GPR120 activated by ω-3 PUFAs may contribute to maintain pregnancy by regulating decidualization. We tested this hypothesis by examining the expression level of GPR120 in human decidua tissues of spontaneous abortions and the effects of GPR120 agonist and antagonists in LPS or RU486 induced mouse abortions. We observed that GPR120 was downregulated in abortion decidua and DSCs, which might be relevant to defective decidualization. We found that mice with inhibition or deletion of GPR120 appeared to be more sensitive to LPS or RU486 induced abortion while activation of GPR120 could ameliorate the abortion symptoms caused by LPS. The augmentation of decidualization by GPR120 was also verified by in vitro and in vivo experiments, indicating a positive role of GPR120 in maintaining decidualizaiton and pregnancy. Recently, the significance of metabolism in decidualization has been emphasized. It was demonstrated that Warburg-like glycolysis and lactate shuttle play critical roles during decidualization in mice [5]. While another study described the importantce of fatty acid beta-oxidation in decidualization and embryo implantation of human and mice [31]. However, the regulatory mechanisms of metabolism during decidualization still need to be explored. In the present study, we found that glucose metabolism mediated the function of GPR120 in decidualization while fatty acid beta-oxidation was not affected by GPR120 during decidualizaton (data not shown). Consistent with a previous study [32], GLUT1 was found to be abundantly expressed in HESCs and its expression determined the efficiency of glucose uptake during decidualization. Importantly, GPR120 could upregulate GLUT1 and subsequently the glucose uptake. Moreover, G6PD, the key enzyme in PPP, was upregulated by GPR120, indicating the importance of PPP in mediating the role of GPR120 in augmenting decidualization. PPP is the significant glucose metabolism pathway to supply ribose 5-phophate and NADPH for biosynthesis of nucleic acid, fatty caids and amino acids, etc., in order to guarantee cell proliferation, differentiation, activation and other functions [33,34]. It has been described that maternal G6PD deficiency is embryonic letal and would cause severe abnormalities in the placenta [35]. Moreover, blockade of the PPP impaired decidualization and implantation [36]. Therefore, it is vital to preserve proper PPP flux during pregnancy. Given the regulatory role of GPR120 on G6PD and PPP shown in the present study, it can be hypothesized that downregulation of GPR120 damages the process of PPP, which causes defective decidualization and poor pregnancy outcome. While the upregulation of PPP by GPR120 could improve biosynthesis required for decidualization.