Muscle-specific PPARγ-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones

Abstract

Activation of peroxisome proliferator-activated receptor γ (PPARγ) by thiazolidinediones (TZDs) improves insulin resistance by increasing insulin-stimulated glucose disposal in skeletal muscle. It remains debatable whether the effect of TZDs on muscle is direct or indirect via adipose tissue. We therefore generated mice with muscle-specific PPARγ knockout (MuPPARγKO) using Cre/loxP recombination. Interestingly, MuPPARγKO mice developed excess adiposity despite reduced dietary intake. Although insulin-stimulated glucose uptake in muscle was not impaired, MuPPARγKO mice had whole-body insulin resistance with a 36% reduction (P < 0.05) in the glucose infusion rate required to maintain euglycemia during hyperinsulinemic clamp, primarily due to dramatic impairment in hepatic insulin action. When placed on a high-fat diet, MuPPARγKO mice developed hyperinsulinemia and impaired glucose homeostasis identical to controls. Simultaneous treatment with TZD ameliorated these high fat-induced defects in MuPPARγKO mice to a degree identical to controls. There was also altered expression of several lipid metabolism genes in the muscle of MuPPARγKO mice. Thus, muscle PPARγ is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action. The tissue crosstalk mediating these effects is perhaps due to altered lipid metabolism in muscle.

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.…”

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

“…TLR4 inactivation supports higher insulin sensitivity and lipogenesis in WAT after 22 weeks of high-fat diet but not in skeletal muscle We hypothesised that TLR4 inactivation could affect insulin sensitivity of insulin target tissues in Table 3 [28], as is insulin sensitivity [29]. Insulinstimulated glucose utilisation was significantly higher in subcutaneous adipose tissue of C3H/HeJ than in that of C3H/HeOuJ mice (Fig.…”

Nuclear receptors, mitochondria and lipid metabolism

“…The importance of PPARγ outside the adipose tissue is highlighted by mice with skeletal muscle-specific loss of PPARγ that had 80% reductions in insulin-stimulated glucose disposal rates that did not improve with TZD treatment ). Other muscle-specific studies, with different PPARγ mutations, showed some TZD sensitivity (Norris et al 2003).…”