Adipose tissue-specific PPARgamma deficiency increases resistance to oxidative stress.

The nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARgamma) critically regulates adipogenesis and lipogenesis. Obesity is closely associated with increased oxidative stress, and pharmacological activation of PPARgamma by its ligands significantly suppresses oxidative stress in cultured adipocytes. On the other hand, a PPARgamma2(Pro12Ala) polymorphism, which decreases receptor transcription activity, is associated with lower body mass index and increased insulin sensitivity in humans. This mutation is also found to be positively associated with increased human lifespan. Here we show that adipose tissue-specific PPARgamma heterozygous mice, which exhibit significant improvement in insulin sensitivity in skeletal muscle, show increased resistance to paraquat-induced oxidative stress. The enhanced oxidative stress tolerance is associated with significant upregulation of antioxidant genes in white adipose tissue and skeletal muscle whereas prooxidant genes are not changed. This is also associated with a significant increase in adipose tissue of Foxo3a, a transcription factor that is known to regulate clearance of reactive oxygen species. Consistently, Foxo3a dependent genes are significantly upregulated in adipose tissue. These data implicate adipose tissue PPARgamma in the regulation of oxidative stress, which may underlie extended lifespan in humans bearing PPARgamma2(Pro12Ala) mutation.