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  • The intracellular signaling that mediates the adipogenesis i

    2022-06-23

    The intracellular signaling that mediates the adipogenesis induced by GPR120 still remains largely unknown. In the present study we showed that TUG-891 induced the activation of [Ca2+]i and ERK1/2 signaling in 3T3-L1 cells. Moreover, incubation of TUG-891 combined with BAPTA-AM or U0126 abolished TUG-891-induced adipogenesis. From our results, we speculate that [Ca2+]i and ERK1/2 signaling are involved in GPR120-induced adipogenesis. Activation of ERK1/2 is likely to facilitate adipogenesis at the mitotic clonal expansion (MCE) stage, but block adipogenic gene expression in later stage of adipogenesis (Bost et al., 2005a, Burgermeister and Seger, 2007, Prusty et al., 2002). MCE is a required phase in the adipogenic program (Otto and Lane, 2005, Tang and Lane, 2012). The differentiation of 3T3-L1 protein kinase has two rounds of MCE. The first round is finished in 24–36 h after adipogenic induction and another round is completed in 48–60 h, which results in an increase >2-fold in cell number at day 2 (Kim et al., 2007, Tang et al., 2003). In addition, there is evidence suggesting that the [Ca2+]i appears to exert a biphasic regulatory function in the preadipocyte differentiation. Both in mice and human preadipocyte cells, the increase of [Ca2+]i in early stages before 2 days suppresses the adipogenic differentiation, whereas it promotes adipogenic differentiation in the later stage (Liu and Clipstone, 2007, Mora et al., 2002, Neal and Clipstone, 2002, Ntambi and Takova, 1996). In 3T3-L1 cells, GPR120 was expressed from 2 days after adipogenic induction, which is the beginning of the second round of MCE. These evidences indicate that the activation of [Ca2+]i and ERK1/2 by the TUG-891 is favorable for the following terminal differentiation. Recently, a research group reported that GPR120 is activated by low concentration of TUG-891 to promote the adipogenesis of bone marrow mesenchymal stem cells (BMMSC), while higher concentration of TUG-891 fails to facilitate BMMSC adipogenesis (Gao et al., 2015). In this study, 3T3-L1 preadipocyte is known as a determined adipogenic cell line, which is different from BMMSC. Moreover, GPR120 was only slightly expressed at the beginning of the differentiation of 3T3-L1 preadipocytes. These phenomena may result in diverse mechanisms of GPR120 in regulating the adipogenesis of stem cells and preadipocytes. Both our results and those from previous studies of other groups suggest that GPR120 is required for normal adipogenesis (Gotoh et al., 2007, Ichimura et al., 2012). The expression of GPR120 was significantly increased in both subcutaneous (SAT) and visceral (VAT) adipose tissues in the obese individual (Ichimura et al., 2012). However, another group reported that morbidly obese individuals have lower expression of GPR120 protein and mRNA in VAT than lean humans (Rodriguez-Pacheco et al., 2014). That is the discrepancy between studies (Ulven and Christiansen, 2015). In fact, GPR120 plays an important role in systemic homeostasis (Oh et al., 2010, Oh et al., 2014). The GPR120-deficient mice are easy to develop obesity and other obesity metabolic problems with decreased adipocyte adipogenesis and promoted hepatic lipogenesis than the wild type mice (Ichimura et al., 2012). Besides, it seems that the GPR120 expressed in mature adipocytes might induce the production of C16:1n7 palmitoleate, which has been proposed to be a lipid hormone (Cao et al., 2008), to regulate systemic metabolic homeostasis (Ichimura et al., 2012). Chen et al. have reported that C/EBPβ plays a critical role in the regulation of GPR120 expression in 3T3-L1 cells (Chen et al., 2016). It is interesting to know whether C/EBPβ mediates the regulation of fatty acids on GPR120 expression. These results suggest the association between GPR120 and obesity and imply that the role of GPR120 in metabolic regulation is still not fully clarified (Ulven and Christiansen, 2015). In summary, our data demonstrate that synthetic agonist TUG-891-induced GPR120 activation in 2-day differentiated 3T3-L1 adipocytes increases the expression of adipogenic master regulator PPARγ, resulting in the increased expression of lipogenic marker genes and stimulated triglyceride accumulation. GPR120-mediated adipogenesis is transduced via at least one vital [Ca2+]i-ERK1/2 pathway. Our results for the first time demonstrate the signaling involved in GPR120-induced adipogenesis in 3T3-L1 adipocytes. However, further studies are still needed to elucidate the precise mechanism. GPR120 has been proposed as a potential target to treat obesity-related inflammation and diabetes. For the abundant expression of GPR120 in fat tissues (Gotoh et al., 2007), studying the role and mechanism of GPR120 in adipogenesis, interaction between adipocytes and macrophage and production of adiponectin will improve the understanding of the physiological processes manipulated by selective fatty acids and help the development of GPR120-targeted compound to treat obesity related disease.