Roles of peroxisome proliferator-activated receptor delta (PPARδ) in the control of fatty acid catabolism. A new target for the treatment of metabolic syndrome

摘要

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors playing important regulatory functions in development and metabolism. PPARα and PPARγ are the most extensively examined and characterized, mainly because they are activated by marketed hypolipidemic and insulin sensitizer compounds, such as fibrates and thiazolidinediones. It has been established that the third member of the family, PPARδ is implicated in developmental regulations, but until recently, its role in metabolism remained unclear. The availability of specific PPARδ agonists and of appropriate cellular and animal models revealed that PPARδ plays a crucial role in fatty acid metabolism in several tissues. Treatment of obese animals with PPARδ agonists results in normalization of metabolic parameters and reduction of adiposity. Activation of the nuclear receptor promotes fatty acid burning in skeletal muscle and adipose tissue by upregulation of fatty acid uptake, β-oxidation and energy uncoupling. PPARδ is also involved in the adaptive metabolic responses of skeletal muscle to environmental changes, such as long-term fasting or physical exercise, by controlling the number of oxidative myofibers. These observations strongly suggest that PPARδ agonists may have therapeutic usefulness in metabolic syndrome by increasing fatty acid consumption and decreasing obesity.