Insulin Resistance and Metabolic Derangements in Obese Mice Are Ameliorated by a Novel Peroxisome Proliferator-activated Receptor γ-sparing Thiazolidinedione
| Autor: | Nathan Qi, Mayurranjan S. Mitra, William G. McDonald, Angela M. Hall, Brian N. Finck, Kari T. Chambers, Rolf F. Kletzien, Patrick A. Vigueira, Zhouji Chen, Jerry R. Colca |
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| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class Gene Expression Mice Obese Peroxisome proliferator-activated receptor Adipose tissue Inflammation Type 2 diabetes Biology Binding Competitive Biochemistry Rosiglitazone Mice Insulin resistance 3T3-L1 Cells Internal medicine medicine Animals Humans Hypoglycemic Agents Obesity Thiazolidinedione Molecular Biology Cells Cultured Mice Knockout chemistry.chemical_classification Molecular Structure Pioglitazone Reverse Transcriptase Polymerase Chain Reaction Lipogenesis Hep G2 Cells Cell Biology medicine.disease Mice Inbred C57BL PPAR gamma Metabolism Endocrinology chemistry Hepatocytes Female Thiazolidinediones Insulin Resistance medicine.symptom Glycolysis medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 287:23537-23548 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.363960 |
| Popis: | Currently approved thiazolidinediones (TZDs) are effective insulin-sensitizing drugs that may have efficacy for treatment of a variety of metabolic and inflammatory diseases, but their use is limited by side effects that are mediated through ectopic activation of the peroxisome proliferator-activated receptor γ (PPARγ). Emerging evidence suggests that the potent anti-diabetic efficacy of TZDs can be separated from the ability to serve as ligands for PPARγ. A novel TZD analog (MSDC-0602) with very low affinity for binding and activation of PPARγ was evaluated for its effects on insulin resistance in obese mice. MSDC-0602 treatment markedly improved several measures of multiorgan insulin sensitivity, adipose tissue inflammation, and hepatic metabolic derangements, including suppressing hepatic lipogenesis and gluconeogenesis. These beneficial effects were mediated at least in part via direct actions on hepatocytes and were preserved in hepatocytes from liver-specific PPARγ−/− mice, indicating that PPARγ was not required to suppress these pathways. In conclusion, the beneficial pharmacology exhibited by MSDC-0602 on insulin sensitivity suggests that PPARγ-sparing TZDs are effective for treatment of type 2 diabetes with reduced risk of PPARγ-mediated side effects. Background: Thiazolidinediones may have insulin-sensitizing effects independent of the nuclear receptor PPARγ. Results: A novel PPARγ-sparing thiazolidinedione ameliorated insulin resistance and inflammation in obese mice. Conclusion: The insulin-sensitizing effects of thiazolidinediones are separable from the ability to bind PPARγ. Significance: Identification of other molecular targets of thiazolidinediones may generate new therapeutics for treatment of insulin resistance and diabetes. |
| Databáze: | OpenAIRE |
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