Peroxisome proliferator-activated receptor β/δ as a therapeutic target for metabolic diseases

Abstract

The peroxisome proliferator-activated receptor (PPAR) family comprises three distinct isotypes: PPARα, PPARβ/δ and PPARγ. PPARs are nuclear hormone receptors that mediate the effects of fatty acids and their derivatives at the transcriptional level. Until recently, the characterisation of the important role of PPARα in fatty acid oxidation and of PPARγ in lipid storage contrasted with the sparse information concerning PPARβ/δ. However, evidence is now emerging for a role of PPARβ/δ in tissue repair and energy homeostasis. Experiments with tissue-specific overexpression of PPARβ/δ or treatment of mice with selective PPARβ/δ agonists demonstrated that activation of PPARβ/δ in vivo increases lipid catabolism in skeletal muscle, heart and adipose tissue and improves the serum lipid profile and insulin sensitivity in several animal models. PPARβ/δ activation also prevents the development of obesity and improves cholesterol homeostasis in obesity-prone mouse models. These new insights into PPARβ/δ functions suggest that targeting PPARβ/δ may be helpful for treating disorders associated with the metabolic syndrome. Although these perspectives are promising, several independent and contradictory reports raise concerns about the safety of PPARβ/δ ligands with respect to tumourigenic activity in the gut. Thus, it appears that further exploration of PPARβ/δ functions is necessary to better define its potential as a therapeutic target.