Obese mice lacking inducible nitric oxide synthase are sensitized to the metabolic actions of peroxisome proliferator-activated receptor-gamma agonism.

Description

This study tested the hypothesis that inducible nitric oxide synthase (iNOS), a key inflammatory mediator in obesity, modulates peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activity in insulin-target tissues by investigating the metabolic and glucoregulatory effects of the thiazolidinedione rosiglitazone in both wild-type and iNOS-deficient obese mice. The authors found that rosiglitazone improved insulin sensitivity and insulin signalling in the muscle of wild-type obese mice and obese mice lacking iNOS but failed to improve glucose tolerance and liver insulin signalling in wild-type obese mice. Moreover, the genotype-specific effect of rosiglitazone on glucose tolerance was linked to a marked propensity to raise plasma adiponectin levels. Accordingly, rosiglitazone treatment increased AMPK activity in muscle and liver only in obese mice lacking iNOS, which could be explained by the failure of rosiglitazone to raise plasma adiponectin in its high-molecular weight form (responsible for the insulin-sensitizing action, particularly in the liver) in wild-type obese mice. The study findings identified the iNOS/NO pathway as a critical modulator of PPAR-gamma activation and plasma adiponectin levels and demonstrated that the invalidation of iNOS improves the efficacy of PPAR-gamma agonism in obese insulin-resistant mice.