Chenodeoxycholic acid improves insulin resistance by FXR-mediated regulation of intestinal GLP-1 in high-fat diet mice

To explore the effect of chenodeoxycholic acid (CDCA) on the expression of glucagon-like peptide-1 (GLP-1) in the intestine of mice induced by high-fat diet (HFD) through farnesoid X receptor (FXR), and investigate the related mechanism.

Forty C57BL/6 mice were divided into control group, HFD group, HFD+CDCA group, HFD+Z-Gug (FXR antagonist) group, and HFD+CDCA+Z-Gug group, with 8 animals in each group. During intervention for 8 weeks, body weight and 24-hour food intake were measured every week. At the 8th week, oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT) were conducted. After the mice were sacrificed, the serum levels of GLu, TG, CHO, LDL-C and HDL-C were detected; the expression levels of GLP-1 and FXR in intestinal tissues were detected by immunofluorescence assay; and the mRNA levels of TNF-α, IL-6, IL-1β, Gcg and FXR were detected by RT-qPCR; the serum level of GLP-1 was detected by ELISA, and the proportion of intraepithelial lymphocytes (IELs) subsets and the expression of CD26/DPP4 were detected by flow cytometry.

Compared with the control group, the HFD group had increased body weight, abnormal serum glucose and lipid metabolism, impaired oral glucose tolerance, and weakened secretion of gastrointestinal hormones (P<0.05), enhanced FXR expression at mRNA and protein levels, declined Gcg mRNA level and GLP-1 secretion level (P<0.05), increased mRNA levels of intestinal inflammatory factors TNF-α, IL-6 and IL-1β (P<0.05), raised proportions of TCRαβ⁺ IELs, TCRαβ⁺CD8αα⁺ IELs, and TCRαβ⁺CD8αβ⁺ IELs but reduced proportion of TCRγδ⁺IELs, and increased total CD26/DPP4 expression in IELs (P<0.05). Compared with the HFD group, HFD+CDCA treatment resulted in significantly increased body weight, impaired oral glucose tolerance, decreased secretion of gastrointestinal hormones, increased FXR mRNA and protein expression, and decreased Gcg mRNA expression and GLP-1 secretion (P<0.05); decreased proportions of TCRαβ⁺ IELs, TCRαβ⁺CD8αα⁺ IELs and TCRααβ⁺CD8αβ⁺ IELs but increased proportion of TCRγδ⁺ cells in IELs, and increased expression of total CD26/DPP4 in IELs (P<0.05), which were significantly improved after Z-Gug intervention (P<0.05).

CDCA may inhibit the expression and secretion of GLP-1 in intestinal tissue by activating FXR, and reduce the secretion of GLP-1. At the same time, CDCA may inhibit the expression of related inflammatory factors, regulate the proportions of IELs subsets, up-regulate the expression level of CD26/DPP4, promote the degradation of GLP-1 and aggravate insulin resistance.