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PPAR ResearchVolume 2008 2008, Article ID 736362, 2 pages

EditorialDepartment of Biology, Metabolex Inc., Hayward, CA 94545, USA

Received 30 December 2008; Accepted 30 December 2008

Copyright © 2008 Francine M. Gregoire. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The biology of Peroxisome proliferator-activated receptor PPAR alpha αand gamma γ has been intensely scrutinized for the last 20 years and the clinical useof both PPAR-α fibrates and PPAR-γ thiazolididionesagonists has led to the understanding of their key role in the treatment ofhypertriglyceridemia and type 2 diabetes mellitus 1, 2. In contrast, the understanding of PPAR delta δ biology still lags behind. The identification of small moleculeagonists for PPAR-δ has shed some light on thefunction of this ubiquitously expressed receptor in preclinical models andearly clinical studies 3. They have revealed the multiple benefits of PPAR-δactivation on lipid disorders, diabetes, and inflammation 3, 4. However, synthetic PPAR-δ agonists have yet to bemarketed for clinical use in humans, partly due to the burdenassociated with their clinical development 3.

In this special issue of PPAR Research, thebroad potential of PPAR-δ agonistsfor the treatment of metabolic disease is highlighted by 3 key articles. Theyinclude a review from de Lange et al. on the regulation of the oxidative capacity of muscle by PPAR-δ, anarticle by Perreault et al. which tackles opportunities and issues with thedevelopment of PPAR-δ agonist for the treatment ofobesity, and finally a review from Wang that addresses the effect of PPAR-δ activationon vascular pathophysiological processes. A key question regarding the resultof PPAR-δactivation, either via natural or via synthetic ligands, is its effect on cellproliferation and the risk of inducing cancer. This has been an area of intensedebate as both pro- and antitumorigenic effectshave been reported. This topic is concisely reviewed in this issue by Muller etal. Last but not least, two interesting and not well-characterized portions ofPPAR-δbiology are presented. First, as PPAR-δ is expressed at high levelin the brain, Hall et al. investigate the potentialneuroprotective role of PPAR-δ activation in thisorgan. Second, although the role ofPPAR-δ inembryo implantation was recognized early on with studies in knockout mice 5,the reproductive functions of PPAR-δ are still unclear. Thistopic and the projected potential applications of PPAR-δligands in assisted reproductive technology are addressed in Huang’s review.

Taken together, it isobvious that there is an urgent need for additional basic research to bettercharacterize PPAR-δ function. The currentavailability of synthetic ligands should help to further dissect PPAR-δ-mediated responses in the brain as well as in other functions not addressed inthis issue, including gut and skin homesotasis. Although challenges for the development of PPAR-δagonists remains, they clearly holdgreat therapeutic promise, ashighlighted by recent clinical findings indicating that MBX-8025, one of themost advanced PPAR-δ agonists currently in phaseII clinical trial for dyslipidemia, displays hypolipidemic features not observed with the currentlyavailable dyslipidemia therapies 6, 7.

Francine M. Gregoire

References

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Author: Francine M. Gregoire

Source: https://www.hindawi.com/



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