Muscle-specific Pparg deletion causes insulin resistance

Abstract

Thiazolidinediones (TZDs) are insulin-sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Although muscle is the major organ responsible for insulin-stimulated glucose disposal, PPAR-gamma is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre-loxP system to knock out Pparg, the gene encoding PPAR-gamma, in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR-gamma in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic-euglycemic clamp technique, the in vivo insulin-stimulated glucose disposal rate (IS-GDR) was reduced by approximately 80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR-gamma in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs.

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

“…Using the Cre-Lox-P-mediated gene targeting, two recent reports described the generation of mice specifically lacking PPARg in muscle and showed that this deletion leads to secondary insulin resistance in the liver and adipose tissue. 18,19 Treatment of this mouse model with troglitazone did not improve skeletal muscle insulin resistance but ameliorated hepatic and adipose insulin sensitivity, supporting the idea that muscle cells directly respond to PPARg agonist treatment, but that local PPARg in muscle is not an essential contributor to systemic antidiabetic effect of TZDs. Ablation of PPARg in mature adipocytes results in improvements of hepatic insulin sensitivity in response to TZD treatment, but did not lower serum triglycerides and free fatty acids.…”

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

“…The question of whether TZDs exert direct effects in muscle and liver has been controversial. In the case of muscle, it has been elegantly addressed by two recent studies of metabolic responses in muscle-specific PPARγ knock-out mouse models [4,32]. There are significant differences between these two models.…”

“…Firstly, TZDs activate peroxisome proliferator-activated receptor (PPAR) γ, a transcription factor predominantly expressed in adipocytes. While there is some evidence that PPARγ plays a functional role in skeletal muscle [4], its expression levels in muscle and liver are extremely low compared with adipocytes. Secondly, TZDs lower circulating levels of lipids and lipid accumulation in non-adipose tissues including skeletal and cardiac muscle, liver and pancreatic islets [2,5,6,7,8,9].…”

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

“…The nuclear receptor for thiazolidinedione, peroxisome proliferator-activated receptor (PPAR) γ, is highly expressed in adipocytes suggesting that thiazolidinediones mainly exert their insulin-sensitising effect through the adipose tissue although controversial results have been published [1,2]. Thiazolidinediones improve insulin sensitivity both in man and in different animal models of insulin resistance [3,4].…”