Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas

Figure 1 Peroxisome proliferator-activated receptors mechanisms of action. Proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate gene expression through two different mechanisms. A: PPAR-retinoid X receptor heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements to trigger target genes transcription (transactivation). PPARs’ target genes include thermogenic [Ucp1, PPAR-gamma coactivator 1 alpha (Pgc1α), and PR domain containing 16 (Prdm16)], mitochondrial and peroxisomal [carnitine palmitoyltransferase I (Cpt1), peroxisomal acyl-coenzyme A oxidase (Acox), and pyruvate dehydrogenase kinase 4 (Pdk4)], anti-inflammatory (Adiponectin), insulin-sensitizing [glucose transporter 2 (Glut2), Glut4], and adipocyte metabolism [Cd36, adipocyte protein 2 (Ap2), lipoprotein lipase (Lpl), Perilipin, and acetyl CoA synthetase (Acs)] genes; B: PPARs regulate gene expression through transrepression, a DNA-independent mechanism. For example, PPARs inhibits the activity of nuclear factor kappa b and enzymes, yielding anti-inflammatory effects. Abbreviations: Uncoupling protein 1, Pgc1α, Prdm16, Cpt1, peroxisomal Acox, Pdk4, Glut, Ap2, Lpl, and Acs, inducible nitric oxide synthase, nuclear factor kappa B, and ciclooxigenase-2. PPARs: Peroxisome proliferator-activated receptors; RXR: Retinoid X receptor; PPRE: PPAR-responsive elements; NF-κB: Nuclear factor kappa B; iNOS: Inducible nitric oxide synthase; COX-2: Ciclooxigenase-2.