prostaglandin-d2 and Insulin-Resistance

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

PPARgamma has been recently described as being a gene of susceptibility for Intestinal Bowel Diseases (IBD) as NOD2/CARD15 gene. IBD are pathologies due to an abnormal immune response, in genetically predisposed patients, to the bacteria of the intestinal flora. PPARgamma, known for its significant role in adipogenesis, is strongly expressed by the epithelial cells of the colon mucosa. PPARgamma is implicated in the regulation of inflammation. Indeed, agonists of this nuclear receptor decrease strongly the intensity of inflammation during experimental colitis induced by chemical agents. A deficit of PPARgamma in patients with ulcerative colitis has been highlighted, that could in part explain the acute inflammation. In addition, bacteria, including those of the commensal flora, are able to regulate PPARgamma. Toll Like Receptor-4 (TLR-4), responsible for the recognition of bacterial motif as lipopolysaccharide (LPS), is implicated in PPARgamma regulation and its anti-inflammatory properties. All these arguments make of PPARgamma a very interesting therapeutic target for the treatment of IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bacterial Physiological Phenomena; Colitis, Ulcerative; Crohn Disease; Eicosanoids; Fatty Acids, Omega-3; Homeostasis; Humans; Inflammation; Inflammatory Bowel Diseases; Insulin Resistance; Intestinal Mucosa; Ligands; Lipid Metabolism; Mice; PPAR gamma; Prostaglandin D2; Thiazolidinediones; Toll-Like Receptor 4

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

The steroid receptor coactivator 1 (SRC1) regulates key metabolic pathways, including glucose homeostasis. SRC1(-/-) mice have decreased hepatic expression of gluconeogenic enzymes and a reduction in the rate of endogenous glucose production (EGP). We sought to determine whether decreasing hepatic and adipose SRC1 expression in normal adult rats would alter glucose homeostasis and insulin action. Regular chow-fed and high-fat-fed male Sprage-Dawley rats were treated with an antisense oligonucleotide (ASO) against SRC1 or a control ASO for 4 wk, followed by metabolic assessments. SRC1 ASO did not alter basal EGP or expression of gluconeogenic enzymes. Instead, SRC1 ASO increased insulin-stimulated whole body glucose disposal by ~30%, which was attributable largely to an increase in insulin-stimulated muscle glucose uptake. This was associated with an approximately sevenfold increase in adipose expression of lipocalin-type prostaglandin D2 synthase, a previously reported regulator of insulin sensitivity, and an approximately 70% increase in plasma PGD2 concentration. Muscle insulin signaling, AMPK activation, and tissue perfusion were unchanged. Although GLUT4 content was unchanged, SRC1 ASO increased the cleavage of tether-containing UBX domain for GLUT4, a regulator of GLUT4 translocation. These studies point to a novel role of adipose SRC1 as a regulator of insulin-stimulated muscle glucose uptake.

Topics: Adipose Tissue; Animals; Biological Transport; Diet, High-Fat; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Glucose Intolerance; Glucose Transporter Type 4; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Intramolecular Oxidoreductases; Lipocalins; Liver; Male; Muscle, Skeletal; Nuclear Receptor Coactivator 1; Oligodeoxyribonucleotides, Antisense; Phosphoenolpyruvate Carboxykinase (GTP); Prostaglandin D2; Protein Interaction Domains and Motifs; Proteolysis; Rats, Sprague-Dawley

Thiazolidinedione and isoxazolidinedione insulin sensitizers activate peroxisome proliferator-activated receptor gamma (PPAR gamma). Some thiazolidinediones modify ion channels in smooth muscles; however, the mechanism by which their actions occur has not been clarified. We, thus, examined the effects of three thiazolidinediones (troglitazone, pioglitazone, and rosiglitazone) and isoxazolidinedione (JTT-501), as well as an intrinsic ligand for PPAR gamma, 15-deoxy-Delta(12,14) prostaglandin J(2) (prostaglandin J(2)), on voltage-operated Ca(2+) currents (I(Ca)), voltage-dependent K(+) currents (I(Kv)), and Ca(2+)-activated K(+) currents (I(Kca)), to clarify whether a thiazolidinedione structure or PPAR gamma activation is related to their actions on ion channels. The whole-cell patch clamp method was used to record currents in smooth muscle cells from guinea-pig mesenteric arteries. Thiazolidinediones inhibited I(Ca) in a dose-dependent manner (troglitazone>pioglitazone=rosiglitazone). Troglitazone (> or =1 microM) and rosiglitazone (100 microM), but not pioglitazone, inhibited I(Kv). Rosiglitazone (> or =10 microM) enhanced, troglitazone (> or =1 microM) inhibited, and pioglitazone did not affect I(Kca). A high concentration of JTT-501 (100 microM) inhibited I(Ca), I(Kv), and I(Kca) to a similar extent. Prostaglandin J(2) enhanced I(Kca), but affected neither I(Ca) nor I(Kv). In summary, the three thiazolidinediones and isoxazolidinedione act differently on Ca(2+) and K(+) channels in vascular smooth muscle. The action of thiazolidinediones on I(Ca) could be attributed to specific regions of the molecules and not to activation of PPAR gamma. Involvement of PPAR gamma activation in the stimulation of I(Kca) is possible but should be tested further.

Topics: Analysis of Variance; Animals; Barium; Calcium; Chromans; Dose-Response Relationship, Drug; Electric Stimulation; Female; Guinea Pigs; Humans; Insulin Resistance; Ion Channels; Isoxazoles; Membrane Potentials; Muscle, Smooth, Vascular; Pioglitazone; Potassium Channels; Prostaglandin D2; Rosiglitazone; Thiazoles; Thiazolidinediones; Troglitazone

Recent studies have identified a beta-cell insulin receptor that functions in the regulation of protein translation and mitogenic signaling similar to that described for insulin-sensitive cells. These findings have raised the novel possibility that beta-cells may exhibit insulin resistance similar to skeletal muscle, liver, and fat. To test this hypothesis, the effects of tumor necrosis factor-alpha (TNFalpha), a cytokine proposed to mediate insulin resistance by interfering with insulin signaling at the level of the insulin receptor and its substrates, was evaluated. TNFalpha inhibited p70(s6k) activation by glucose-stimulated beta-cells of the islets of Langerhans in a dose- and time-dependent manner, with maximal inhibition observed at approximately 20-50 ng/ml, detected after 24 and 48 h of exposure. Exogenous insulin failed to prevent TNFalpha-induced inhibition of p70(s6k), suggesting a defect in the insulin signaling pathway. To further define mechanisms responsible for this inhibition and also to exclude cytokine-induced nitric oxide (NO) as a mediator, the ability of exogenous or endogenous insulin +/- inhibitors of nitric-oxide synthase (NOS) activity, aminoguanidine or N-monomethyl-L-arginine, was evaluated. Unexpectedly, TNFalpha and also interleukin 1 (IL-1)-induced inhibition of p70(s6k) was completely prevented by inhibitors that block NO production. Western blot analysis verified inducible NOS (iNOS) expression after TNFalpha exposure. Furthermore, the ability of IL-1 receptor antagonist protein, IRAP, to block TNFalpha-induced inhibition of p70(s6k) indicated that activation of intra-islet macrophages and the release of IL-1 that induces iNOS expression in beta-cells was responsible for the inhibitory effects of TNFalpha. This mechanism was confirmed by the ability of the peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta12, 14-prostaglandin J2 to attenuate TNFalpha-induced insulin resistance by down-regulating iNOS expression and/or blocking IL-1 release from activated macrophages. Overall, TNFalpha-mediated insulin resistance in beta-cells is characterized by a global inhibition of metabolism mediated by NO differing from that proposed for this proinflammatory cytokine in insulin-sensitive cells.

Topics: Animals; Chromans; Guanidines; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phosphorylation; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Ribosomal Protein S6 Kinases; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone; Tumor Necrosis Factor-alpha

Thiazolidinediones (TZDs) such as BRL 49653 are a class of antidiabetic agents that are agonists for the peroxisome proliferator-activated nuclear receptor (PPAR-gamma2). In vivo, TZDs reduce circulating levels of free fatty acids (FFAs) and ameliorate insulin resistance in individuals with obesity and NIDDM. Adipocyte production of TNF-alpha is proposed to play a role in the development of insulin resistance, and because BRL 49653 has been shown to antagonize some of the effects of TNF-alpha, we examined the effects of TNF-alpha and BRL 49653 on adipocyte lipolysis. After a 24-h incubation of TNF-alpha (10 ng/ml) with 3T3-L1 adipocytes, glycerol release increased by approximately 7-fold, and FFA release increased by approximately 44-fold. BRL 49653 (10 pmol/l) reduced TNF-alpha-induced glycerol release by approximately 50% (P < 0.001) and FFA release by approximately 90% (P < 0.001). BRL 49653 also reduced glycerol release by approximately 50% in adipocytes pretreated for 24 h with TNF-alpha. Prolonged treatment (5 days) with either BRL 49653 or another PPAR-gamma2 agonist, 15-d delta-12,14-prostaglandin J2 (15-d deltaPGJ2), blocked TNF-alpha-induced glycerol release by approximately 100%. Catecholamine (isoproterenol)-stimulated lipolysis was unaffected by BRL 49653 and 15-d deltaPGJ2. BRL 49653 partially blocked the TNF-alpha-mediated reduction in protein levels of hormone-sensitive lipase and perilipin A, two proteins involved in adipocyte lipolysis. These data suggest a novel pathway that may contribute to the ability of the TZDs to reduce serum FFA and increase insulin sensitivity.

Topics: 3T3 Cells; Adipocytes; Animals; Carrier Proteins; Fatty Acids, Nonesterified; Glycerol; Hypoglycemic Agents; Insulin Resistance; Lipolysis; Mice; Perilipin-1; Phosphoproteins; Prostaglandin D2; Rosiglitazone; Sterol Esterase; Thiazoles; Thiazolidinediones; Tumor Necrosis Factor-alpha