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

The peroxisome proliferator-activated receptor (PPAR) family comprises three distinct isotypes: PPAR alpha, PPAR beta/delta and PPAR gamma. 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 PPAR alpha in fatty acid oxidation and of PPAR gamma in lipid storage contrasted with the sparse information concerning PPAR beta/delta. However, evidence is now emerging for a role of PPAR beta/delta in tissue repair and energy homeostasis. Experiments with tissue-specific overexpression of PPAR beta/delta or treatment of mice with selective PPAR beta/delta agonists demonstrated that activation of PPAR beta/delta 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. PPAR beta/delta activation also prevents the development of obesity and improves cholesterol homeostasis in obesity-prone mouse models. These new insights into PPAR beta/delta functions suggest that targeting PPAR beta/delta 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 PPAR beta/delta ligands with respect to tumourigenic activity in the gut. Thus, it appears that further exploration of PPAR beta/delta functions is necessary to better define its potential as a therapeutic target.