1325-P: Study on the Mechanism of Activating Macrophages TGR5 on Glucose Metabolism during Pregnancy

Abstract

Purpose: To explore a new mechanism of improving glucose homeostasis in pregnancy through activation of Takeda G protein-coupled receptor 5 (TGR5) in bone marrow derived macrophages (BMDM) from gestational diabetes mellitus (GDM) model mouse and observation the changes of macrophages migration, inflammatory factors and chemokines expression and secretion, and the expression of Proprotein Convertase 1/3 (PC1/3). Methods: INT-777 was used as TGR5 agonist and LPS was used as inducer for macrophage polarization to M1. Primary bone marrow cells were extracted from GDM model mouse and were induced into macrophages. The macrophages activity and migration were detected by cck-8 tests and Transwell assay respectively when macrophages were treated with INT-777. The expression and secretion levels of inflammatory factors and chemokines in macrophages were detected by real-time PCR, cytometric bead array and ELISA, and the expression levels of PC1/3 was detected by Western blot when macrophages were treated both with INT-777 and lipopolysaccharide (LPS). Results: TGR5 activation of macrophages by INT-777 increased cell activity (P < 0.01) and decreased cell migration (P < 0.001). Moreover, the mRNA levels of inflammatory cytokines and chemokines including IL-1β, IL-6, TNF-α, CCL2, CCL4, CCL5 and CCL7 mRNA were significantly decreased (All P < 0.05), the secretion levels of inflammatory cytokines and chemokines including IL-6, TNF-α, MCP-1, CCL2, CCL3 and CCL4 were significantly decreased (All P < 0.05) and the expression of PC1/3 was increased (P < 0.05) in INT-777 + LPS treated macrophages, compared with LPS treated macrophages only. Conclusions: Activation of TGR5 in BMDM can effectively inhibit the macrophage polarization to M1, including inhibiting inflammatory factors expression and secretion. Moreover, activation of TGR5 can inhibit macrophage chemokine expression and secretion, cell migration and can upregulate PC1/3 expression. Disclosure J. Li: None. F. Liu: None. Funding National Natural Science Foundation of China (81770802)