[PPARgamma and metabolic syndrome]

Abstract

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been suggested to play crucial roles in metabolic diseases such as hyperlipidemia, insulin resistance, and diabetes. The three PPAR subtypes, alpha, beta, and beta/delta, have distinct expression patterns. We have investigated the role of PPARgamma in the pathogenesis of type 2 diabetes. Heterozygous PPARgamm-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy on a high-fat diet. A Pro12Ala polymorphism in the human PPARgamma2 gene, which has been reported to cause a reduction in PPARy activity, was associated with a decreased risk of type 2 diabetes in various ethnic groups including Japanese subjects. Consistent with these results, moderate reduction of PPARgamma activity by RXR antagonist decreased the triglyceride content of white adipose tissue (WAT)/muscle/liver, due to an increase in fatty-acid combustion and a decrease in lipogenesis, thereby ameliorating high-fat diet-induced obesity and insulin resistance. By contrast, potent activation of PPARy by thiazolidinedione (TZD) stimulated adipocyte differentiation and apoptosis, thereby preventing adipocyte hypertrophy, which is associated with the alleviation of insulin resistance, presumably due to decreases in FFA, and TNFa, and the up-regulation of adiponectin. TZD increased the triglyceride content of WAT, but decreased that of the liver/muscle, leading to the amelioration of insulin resistance at the expense of obesity. It should also be noted that TZD has an anti-atherogenic effect in vivo. Uncovering the regulatory mechanisms and transcriptional targets of PPARgamma will provide insights into the pathogenesis of metabolic syndrome and offer valuable information for rational drug design.