PPAR gamma/RXR as a molecular target for diabetes

Type 2 diabetes is associated with insulin resistance in peripheral tissues , such as muscle and fat. Novel therapies that improve insulin action inclu de ligands that bind and activate the nuclear receptors peroxisome prolifer ator activating receptor gamma (PPAR gamma) and retinoid X receptor (RXR). PPAR gamma /RXR form heterodimers that regulate transcription of genes invo lved in insulin action, adipocyte differentiation, lipid metabolism and inf lammation. PPAR gamma activators include prostanoids, fatty acids, thiazoli dinediones and N-(2-benzoylphenyl)tyrosine analogues. RXR ligands include n aturally occurring retinoic acid and synthetic rexinoids. Selective ligands for these receptors improve metabolic abnormalities associated with type 2 diabetes, such as hyperglycemia, hyperlipidemia, insulin resistance and ot her cardiovascular risk factors. Although adipose tissue mediates some of t he effects of PPAR gamma /RXR ligands, other tissues also regulate the effe cts of these receptors. The activity of the PPAR gamma /RXR heterodimer is influenced by posttranslational modifications, receptor turnover, polymorph isms, splice variants, coactivators and corepressors. This article reviews recent developments in research on these receptors, with particular emphasi s on metabolic effects, ligand selectivity, structure and regulation of the PPAR gamma /RXR heterodimer.