Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones

Abstract

PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…The same effect was observed after depletion of Cd11c+ cells that correspond to the main M1 macrophage subset in muscle [242]. Inversely, even lean animals with myeloid deletion of PPAR developed muscle insulin resistance, which deteriorated in the obese state due to impaired M2 macrophage polarization [243]. In contrast, myeloid deletion of PPAR/ or TLR4 did not entail any effect on muscle insulin sensitivity [219,230].…”

Inflammation and insulin resistance

“…The relative degree of insulin resistance became more severe when these mice where subjected to HFD compared to HFD-fed controls. Interestingly, the ability of TZD treatment to improve insulin sensitivity was attenuated in these animals, indicating that the anti-inflammatory properties of TZDs in tissueresident macrophages are a component of their insulin-sensitizing effects [55].…”

Adipose tissue inflammation and ectopic lipid accumulation [Review]

“…Indeed, activation of PPARγ by pioglitazone, a thiazolidinedione class of insulin sensitizer, improves the unbalanced M1/M2 phenotype of adipose tissue macrophages in diet-induced obese mice [32]. Interestingly, a recent study suggests that antidiabetic effects of thiazolidinediones may be mediated, at least partly, through PPARγ in macrophages [33]. Moreover, both M1 and M2 markers are detected in circulating monocytes [34,35].…”