Hypoglycemic Action of Thiazolidinediones/Peroxisome Proliferator–Activated Receptor γ by Inhibition of the c-Jun NH2-Terminal Kinase Pathway

Abstract

Type 2 diabetes results from progressive pancreatic ␤-cell dysfunction caused by chronic insulin resistance. Activation of c-Jun NH 2 -terminal kinase (JNK) inhibits insulin signaling in cultured cells and in vivo and thereby promotes insulin resistance. Conversely, the peroxisome proliferator-activated receptor (PPAR) ␥ synthetic ligands thiazolidinediones (TZDs) enhance insulin sensitivity. Here, we show that the TZDs rosiglitazone and troglitazone inhibit tumor necrosis factor-␣-induced JNK activation in 3T3-L1 adipocytes. Our results indicate that PPAR␥ mediates this inhibitory action because 1) it is reproduced by other chemically unrelated PPAR␥ agonist ligands and blocked by PPAR␥ antagonists; 2) it is enhanced by PPAR␥ overexpression; and 3) it is abrogated by PPAR␥ RNA interference. In addition, we show that rosiglitazone inhibits JNK activation and promotes the survival of pancreatic ␤-cells exposed to interleukin-1␤. In vivo, the abnormally elevated JNK activity is inhibited in peripheral tissues by rosiglitazone in two distinct murine models of obesity. Moreover, rosiglitazone fails to enhance insulin-induced glucose uptake in primary adipocytes from ob/ob JNK1 ؊/؊ mice. Accordingly, we demonstrate that the hypoglycemic action of rosiglitazone is abrogated in the diet-induced obese JNK1-deficient mice. In summary, we describe a novel mechanism based on targeting the JNK signaling pathway, which is involved in the hypoglycemic and potentially in the pancreatic ␤-cell protective actions of TZDs/PPAR␥. Diabetes

Liver X Receptors Inhibit Macrophage Proliferation through Downregulation of Cyclins D1 and B1 and Cyclin-Dependent Kinases 2 and 4

“…Nuclear receptor activation has been shown to affect the activity of members of the MAPK family (32,36). Signaling through the MAPKs ERK-1 and -2 is required for macrophage proliferation in response to M-CSF (9, 24).…”

“…JNK activity was measured as described (32). Briefly, cells were lysed with nuclear extract protocols and immunoprecipitated with protein ASepharose and anti-JNK-1 Ab.…”

Involvement of Inducible 6-Phosphofructo-2-kinase in the Anti-diabetic Effect of Peroxisome Proliferator-activated Receptor γ Activation in Mice

“…Dysfunction-Suppression of adipose tissue inflammatory response is one of the major mechanisms by which PPAR␥ activation reverses insulin resistance and corrects hyperglycemia (6,21,46). The effects of PPAR␥ activation on adipose tissue inflammatory signaling and proinflammatory cytokine expression were determined.…”

Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway

“…In PCOS patients, it has been confirmed that metformin treatment decreases hyperandrogenemia, reestablishes the menstrual cycle, affects the endometrial thickness and blood flow, and ultimately improves ovulation, implantation and pregnancy rates (19,20). TZDs are the peroxisome proliferator-activated receptor γ synthetic ligands that regulate cellular functions to decrease insulin resistance (21,22 In a previous study, pioglitazone showed an obvious beneficial effect on insulin sensitivity in patients with impaired fasting glucose and glucose tolerance (23,24). In women with PCOS, pioglitazone treatment was found to improve the irregularities of menses and hirsutism, reduce insulin resistance, increase the ovulation rate and improve hyperandrogenemia (25)(26)(27)(28).…”