A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat.

Abstract

The discovery that peroxisome proliferator-activated receptor (PPAR)-gamma was the molecular target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-gamma in the regulation of carbohydrate and lipid metabolism. Through the use of high-throughput biochemical assays, GW1929, a novel N-aryl tyrosine activator of human PPAR-gamma, was identified. Chronic oral administration of GW1929 or troglitazone to Zucker diabetic fatty (ZDF) rats resulted in dose-dependent decreases in daily glucose, free fatty acid, and triglyceride exposure compared with pretreatment values, as well as significant decreases in glycosylated hemoglobin. Whole body insulin sensitivity, as determined by the euglycemic-hyperinsulinemic clamp technique, was significantly increased in treated animals. Comparison of the magnitude of glucose lowering as a function of serum drug concentrations showed that GW1929 was 2 orders of magnitude more potent than troglitazone in vivo. These data were consistent with the relative in vitro potencies of GW1929 and troglitazone. Isolated perfused pancreas studies performed at the end of the study confirmed that pancreata from vehicle-treated rats showed no increase in insulin secretion in response to a step change in glucose from 3 to 10 mmol/l. In contrast, pancreata from animals treated with GW1929 showed a first- and second-phase insulin secretion pattern. Consistent with the functional data from the perfusion experiments, animals treated with the PPAR-gamma agonist had more normal islet architecture with preserved insulin staining compared with vehicle-treated ZDF rats. This is the first demonstration of in vivo efficacy of a novel nonthiazolidinedione identified as a high-affinity ligand for human PPAR-gamma. The increased potency of GW1929 compared with troglitazone both in vitro and in vivo may translate into improved clinical efficacy when used as monotherapy in type 2 diabetic patients. In addition, the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients.

Effect of heterodimer partner RXRα on PPARγ activation function-2 helix in solution

“…The dissociation constant K d of GW1929 binding to the PPARγ LBD was 19 ± 10 nM by fluorescence titration. This value was similar to the reported halfmaximal activation EC 50 of 9 ± 7 nM for GW1929 [8], suggesting that the purified PPARγ LBD was functional. The gel filtration chromatography of a heterodimer sample and the subsequent SDS-PAGE analysis of the elution fractions showed that the two LBDs were coeluted in a 1:1 molar ratio ( Supplementary Fig.…”

“…The chemical shift-derived secondary structure generally agrees with the crystal structure of the PPARγ LBD-GI262570-coactivator peptide ternary complex [10]. Both GW1929 [8] and GI262570 [10] are N-aryl tyrosine derivatives that were designed to mimic the interactions between the PPARγ H3, H5, H10 and AF-2 helices and the insulin-sensitizing thiazolidinedione (TZD) drug rosiglitazone head group in the crystal structure [11]. Previous NMR study [12] on the PPARγ LBD without (apo) and with rosiglitazone binding showed that the 3D HNCO spectra of the apo-LBD had less than half of the expected crosspeaks, and rosiglitazone binding restored the missing crosspeaks including those in the AF-2 helix and the C-terminus Y477.…”

Adipose Tissue Resistin Expression Is Severely Suppressed in Obesity and Stimulated by Peroxisome Proliferator-activated Receptor γ Agonists

“…Rosiglitazone and GW1929 are full PPAR␥ agonists (8,11). MCC-555 profiles as a low affinity full PPAR␥ agonist in cell-based assays but acts as a potent antidiabetic agent in vivo (12).…”

“…Age (9 weeks)-and glucose-matched male Zucker diabetic fatty rats (Genetic Models, Inc., Indianapolis, IN) were gavaged twice daily for 7 days with vehicle (0.05 M N-methylglucamine), GW1929 (5.0 mg/kg), or rosiglitazone (3.0 mg/kg). Glucose, triglycerides, and non-esterified fatty acids were measured as described previously (8). Insulin-treated animals received a mixture of Humulin®N and Humulin®R (Lilly) by subcutaneous injection and were sacrificed 6 h later.…”

PPARγ : un récepteur nucléaire majeur de l’adipogenèse

“…De ce fait, la cellulose conserve un meilleur degré de polymérisation, ce qui permet d'obtenir un papier de qualité supérieure. De plus, le rendement en pâte est augmenté de 3 % environ, ce qui est considérable, au vu des énormes quantités de papier produites annuellement [7]. Ainsi, ces peupliers à lignines modifiées, tout en diminuant les coûts de production permettent d'obtenir avec un meilleur rendement un papier de plus grande qualité.…”