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PPAR gamma/RXR as a molecular target for diabetes
1Department of Metabolic Diseases, GlaxoSmithKline Inc., 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA.
Abstract:
Type 2 diabetes is associated with insulin resistance in peripheral tissues, such as muscle and fat. Novel therapies that improve insulin action include ligands that bind and activate the nuclear receptors peroxisome proliferator activating receptor gamma (PPAR gamma) and retinoid X receptor (RXR). PPAR gamma/RXR form heterodimers that regulate transcription of genes involved in insulin action, adipocyte differentiation, lipid metabolism and inflammation. PPAR gamma activators include prostanoids, fatty acids, thiazolidinediones and N-(2-benzoylphenyl)tyrosine analogues. RXR ligands include naturally 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 other cardiovascular risk factors. Although adipose tissue mediates some of the effects of PPAR gamma/RXR ligands, other tissues also regulate the effects of these receptors. The activity of the PPAR gamma/RXR heterodimer is influenced by posttranslational modifications, receptor turnover, polymorphisms, splice variants, coactivators and corepressors. This article reviews recent developments in research on these receptors, with particular emphasis on metabolic effects, ligand selectivity, structure and regulation of the PPAR gamma/RXR heterodimer.
Insights
Novel therapies targeting nuclear receptors peroxisome proliferator activating receptor gamma (PPAR gamma) and retinoid X receptor (RXR) show promise for improving insulin action and metabolic abnormalities in type 2 diabetes.
Area of Science:
- Endocrinology and Metabolism
- Molecular Biology
- Pharmacology
Background:
- Type 2 diabetes is characterized by insulin resistance in peripheral tissues.
- Nuclear receptors peroxisome proliferator activating receptor gamma (PPAR gamma) and retinoid X receptor (RXR) are key targets for novel diabetes therapies.
- PPAR gamma/RXR heterodimers regulate genes involved in insulin sensitivity, lipid metabolism, and inflammation.
Purpose of the Study:
- To review recent developments in research on PPAR gamma and RXR.
- To emphasize the metabolic effects, ligand selectivity, structure, and regulation of the PPAR gamma/RXR heterodimer.
Main Methods:
- Review of recent scientific literature on PPAR gamma and RXR.
- Analysis of selective ligands and their impact on metabolic abnormalities.
- Examination of factors influencing PPAR gamma/RXR heterodimer activity.
Main Results:
- Selective ligands for PPAR gamma/RXR improve hyperglycemia, hyperlipidemia, and insulin resistance.
- Adipose tissue and other tissues mediate the effects of these ligands.
- Heterodimer activity is modulated by posttranslational modifications, receptor turnover, polymorphisms, splice variants, coactivators, and corepressors.
Conclusions:
- Targeting PPAR gamma and RXR offers a promising therapeutic strategy for type 2 diabetes.
- Understanding the complex regulation of the PPAR gamma/RXR heterodimer is crucial for developing effective treatments.