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Calls for Activation in Moderation: Lessons from Genetics and Pharmacology
Institut de Génétique et de Biologie Moléculaire et Cellulaire (C.K., J.A.), Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, and Institut Clinique de la Souris (J.A.), Génopole Strasbourg, 67404 Illkirch, France
Correspondence: Address all correspondence and requests for reprints to: Johan H. Auwerz, M.D., Ph.D., Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, IGBMC, Parc d’Innovation, 1, rue Laurent Fries, 67404 Illkirch, France. E-mail: auwerx{at}igbmc.u-strasbg.fr
The peroxisome proliferator-activated receptor 
(PPAR) is a prototypical member of the nuclear receptor superfamily and integrates the control of energy, lipid, and glucose homeostasis. PPAR can bind a variety of small lipophilic compounds derived from metabolism and nutrition. These ligands, in turn, determine cofactor recruitment to PPAR, regulating the transcription of genes in a variety of metabolic pathways. PPAR is the main target of the thiazolidinedione class of insulin-sensitizing drugs, which are currently a mainstay of therapy for type 2 diabetes. However, this therapy has a number of side effects. Here, we review the clinical consequences of PPAR polymorphisms in humans, as well as several studies in mice using general or tissue-specific knockout techniques. We also discuss the recent pharmacological literature describing a variety of new PPAR partial agonists and antagonists, as well as pan-PPAR agonists. The results of these studies have added to the understanding of PPAR function, allowing us to hypothesize a general mechanism of PPAR action and speculate on future trends in the use of PPAR as a target in the treatment of type II diabetes.
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