15-deoxyprostaglandin-j2 and Insulin-Resistance

Topics: Adipocytes; Cell Differentiation; Humans; Insulin Resistance; Ligands; Linoleic Acids; Linoleic Acids, Conjugated; Macrophage Activation; PPAR gamma; Prostaglandin D2

Cyclooxygenase (COX)-2 selective inhibitors suppress non-alcoholic fatty liver disease (NAFLD); however, the precise mechanism of action remains unknown. The aim of this study was to examine how the COX-2 selective inhibitor nimesulide suppresses NAFLD in a murine model of high-fat diet (HFD)‑induced obesity. Mice were fed either a normal chow diet (NC), an HFD, or HFD plus nimesulide (HFD-nime) for 12 weeks. Body weight, hepatic COX-2 mRNA expression and triglyceride accumulation were significantly increased in the HFD group. Triglyceride accumulation was suppressed in the HFD-nime group. The mRNA expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ) and the natural PPARγ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d‑PGJ2) were significantly increased in the HFD group and significantly suppressed in the HFD-nime group. Glucose metabolism was impaired in the HFD group compared with the NC group, and it was significantly improved in the HFD-nime group. In addition, the plasma insulin levels in the HFD group were increased compared with those in the NC group, and were decreased in the HFD-nime group. These results indicate that HFD-induced NAFLD is mediated by the increased hepatic expression of COX-2. We suggest that the production of 15d-PGJ2, which is mediated by COX-2, induces NAFLD and hepatic insulin resistance by activating PPARγ. Furthermore, the mRNA expression of tissue inhibitor of metalloproteinases-1 (TIMP‑1), procollagen-1 and monocyte chemoattractant protein-1 (MCP-1), as well as the number of F4/80-positive hepatic (Kupffer) cells, were significantly increased in the HFD group compared with the NC group, and they were reduced by nimesulide. In conclusion, COX-2 may emerge as a molecular target for preventing the development of NAFLD and insulin resistance in diet-related obesity.

Topics: Animals; Chemokine CCL2; Collagen Type I; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Diet, High-Fat; Gene Expression; Glucose; Immunohistochemistry; Insulin; Insulin Resistance; Kupffer Cells; Liver; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; PPAR gamma; Prostaglandin D2; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides; Tissue Inhibitor of Metalloproteinase-1; Triglycerides