Peroxisome Proliferator-Activated Receptor δ: A Target with a Broad Therapeutic Potential for Drug Discovery

The biology of Peroxisome proliferator-activated receptor (PPAR) alpha (α) and gamma (γ) has been intensely scrutinized for the last 20 years and the clinical use of both PPAR-α (fibrates) and PPAR-γ (thiazolididiones) agonists has led to the understanding of their key role in the treatment of hypertriglyceridemia and type 2 diabetes mellitus [1, 2]. In contrast, the understanding of PPAR delta (δ) biology still lags behind. The identification of small molecule agonists for PPAR-δ has shed some light on the function of this ubiquitously expressed receptor in preclinical models and early clinical studies [3]. They have revealed the multiple benefits of PPAR-δ activation on lipid disorders, diabetes, and inflammation [3, 4]. However, synthetic PPAR-δ agonists have yet to be marketed for clinical use in humans, partly due to the burden associated with their clinical development [3]. In this special issue of PPARResearch, the broad potential of PPAR-δ agonists for the treatment of metabolic disease is highlighted by 3 key articles. They include a review from de Lange et al. on the regulation of the oxidative capacity of muscle by PPAR-δ, an article by Perreault et al. which tackles opportunities and issues with the development of PPAR-δ agonist for the treatment of obesity, and finally a review from Wang that addresses the effect of PPAR-δ activation on vascular pathophysiological processes. A key question regarding the result of PPAR-δ activation, either via natural or via synthetic ligands, is its effect on cell proliferation and the risk of inducing cancer. This has been an area of intense debate as both proand antitumorigenic effects have been reported. This topic is concisely reviewed in this issue by Muller et al. Last but not least, two interesting and not well-characterized portions of PPAR-δ biology are presented. First, as PPAR-δ is expressed at high level in the brain, Hall et al. investigate the potential neuroprotective role of PPAR-δ activation in this organ. Second, although the role of PPAR-δ in embryo implantation was recognized early on with studies in knockout mice [5], the reproductive functions of PPAR-δ are still unclear. This topic and the projected potential applications of PPAR-δ ligands in assisted reproductive technology are addressed in Huang’s review. Taken together, it is obvious that there is an urgent need for additional basic research to better characterize PPARδ function. The current availability of synthetic ligands should help to further dissect PPAR-δ-mediated responses in the brain as well as in other functions not addressed in this issue, including gut and skin homesotasis. Although challenges for the development of PPAR-δ agonists remains, they clearly hold great therapeutic promise, as highlighted by recent clinical findings indicating that MBX-8025, one of the most advanced PPAR-δ agonists currently in phase II clinical trial for dyslipidemia, displays hypolipidemic features not observed with the currently available dyslipidemia therapies [6, 7].