Regulatory role of peroxisome proliferator-activated receptor delta (PPAR delta) in muscle metabolism. A new target for metabolic syndrome treatment?

Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in both developmental and metabolic functions. There are activated by fatty acids, fatty acid metabolites, and synthetic compounds marketed for their lipid-lowering and antidiabetic actions. It was clearly established that activation of PPAR alpha and PPAR gamma, by fibrates and thiazolidinediones, respectively, impair metabolic disorders. The implication of the third member of the PPAR family, PPAR delta, remained evasive until recently. These past few years, it has been demonstrated that treatment with PPAR delta agonists normalizes blood lipids, reduces insulin resistance and adiposity in rodent and primate. Utilization of both cellular and animal models revealed that the nuclear receptor plays a central role in the control of fatty acid burning in adipose tissue and skeletal muscle. Furthermore, PPAR delta appeared to be important for adaptive response of skeletal muscle to environmental changes, such as physical exercise.

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

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors playing important regulatory functions in development and metabolism. PPARalpha and PPARgamma 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, PPARdelta is implicated in developmental regulations, but until recently, its role in metabolism remained unclear. The availability of specific PPARdelta agonists and of appropriate cellular and animal models revealed that PPARdelta plays a crucial role in fatty acid metabolism in several tissues. Treatment of obese animals with PPARdelta 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, beta-oxidation and energy uncoupling. PPARdelta 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 PPARdelta agonists may have therapeutic usefulness in metabolic syndrome by increasing fatty acid consumption and decreasing obesity.