Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor family of transcription factors that mediate a variety of cellular processes, including glucose and lipid metabolism, inflammatory responses, and regulation of apoptotic cell death. They act by binding to specific peroxisome proliferator-response elements (PPREs) on target genes. Three forms of PPARs have been described, which are designated as a , d , and g forms. They contain a DNA binding domain and a ligand-binding domain. The DNA-binding domain contains two zinc finger patterns, which bind to the regulator region of DNA when the receptor is activated. The ligand-binding domain has an extensive secondary structure of several a-helices and a b-sheet. Each form is expressed in different tissues and can be activated by different ligands, most of them being specific for one form of PPAR. PPARa is expressed in skeletal muscle, liver, kidney, and endothelial cells and regulates lipoprotein metabolism. Its transcriptional activity is enhanced in the presence of insulin. PPARd is shown to be widely distributed in animal tissues and is reported to be involved in oligodendrocyte differentiation. It is expressed to higher levels in brain, adipose tissue, and skin. PPARg is the most studied isoform and plays a critical role in adipocyte differentiation and fat deposition.

PPARg is shown to mediate the antidiabetic and adipogenic actions of the thiazolidinediones (TZD), a new class of insulin sensitizers, which are under clinical trials for the treatment of Type II diabetes. TZDs are highly selective, high-affinity ligands of PPARg with minimal activity towards the a and b forms. Although PPARg is expressed in most organs, the level of PPARg mRNA is about 50-fold higher in the adipose tissue. When compared to some natural ligands, such as 15-deoxy-D 12, 14-prostaglandin J₂, TZDs exhibit much higher affinity for PPARg (20 - 400 nM).

PPARs have also been linked to inflammatory response in animals. Leukotrine B4 (LTB4) is shown to bind to PPARa and induce transcription of genes of the w- and b-oxidation pathways, which leads to its own catabolism. Clofibrate that binds to PPARa accelerates catabolism of LTB4 in granulocytes and macrophages. Conversely, PPARa -deficient mice show a prolonged inflammatory response when exposed to LTB4. PPARa also interferes with NF-kB transcription by forming inactive complexes with p65 and by inducing IkBa . PPARg may also play a role in mediating inflammatory response. PPARg ligands are shown to inhibit TNFa , IL-6, and IL-1b expression in monocytes, and block the expression of inducible nitric oxide synthase.

In the cell, PPAR forms a heterodimer with the retinoid X receptor (RXR). When induced by TZDs, a conformational change occurs in the heterodimer and co-repressor complexes are displaced. This promotes binding of the PPAR-RXR complex to specific DNA sequences, PPRE, located in the regulatory regions of target genes. PPREs are commonly found in genes involved in lipid metabolism and energy balance, including those encoding lipoprotein lipase, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, glucokinase, and glucose transporter GLUT4.