Effect of heterozygous PPARγ deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding
| Autor: | Yaacov Barak, Jerrold M. Olefsky, Philip D.G. Miles, Ronald M. Evans |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Aging
Heterozygote medicine.medical_specialty Physiology medicine.drug_class Endocrinology Diabetes and Metabolism medicine.medical_treatment Receptors Cytoplasmic and Nuclear Type 2 diabetes Biology Carbohydrate metabolism Mice Troglitazone Insulin resistance Physiology (medical) Internal medicine medicine Animals Chromans Thiazolidinedione Pancreatic hormone Mice Knockout Insulin medicine.disease Dietary Fats Mice Inbred C57BL Thiazoles Endocrinology Thiazolidinediones Insulin Resistance Adipocyte hypertrophy Metabolism Inborn Errors Transcription Factors medicine.drug |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 284:E618-E626 |
| ISSN: | 1522-1555 0193-1849 |
| Popis: | Peroxisome proliferator-activated receptor-γ (PPARγ) is the target receptor for thiazolidinedione (TZD) compounds, which are a class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. Paradoxically, however, mice deficient in PPARγ ( PPARγ+/−) are more insulin sensitive than their wild-type (WT) littermates, not less, as would be predicted. To determine whether PPARγ deficiency could prevent the development of the insulin resistance associated with increasing age or high-fat (HF) feeding, insulin sensitivity was assessed in PPARγ+/−and WT mice at 2, 4, and 8 mo of age and in animals fed an HF diet. Because TZDs elicit their effect through PPARγ receptor, we also examined the effect of troglitazone (a TZD) in these mice. Glucose metabolism was assessed by hyperinsulinemic euglycemic clamp and oral glucose tolerance test. Insulin sensitivity declined with age for both groups. However, the decline in the PPARγ+/−animals was substantially less than that of the WT animals, such that, by 8 mo of age, the PPARγ+/−mice were markedly more insulin sensitive than the WT mice. This greater sensitivity in PPARγ+/−mice was lost with TZD treatment. HF feeding led to marked adipocyte hypertrophy and peripheral tissue and hepatic insulin resistance in WT mice but also in PPARγ+/−mice. Treatment of these mice with troglitazone completely prevented the adipocyte hypertrophy and normalized insulin action. In conclusion, PPARγ deficiency partially protects against age-related insulin resistance but does not protect against HF diet-induced insulin resistance. |
| Databáze: | OpenAIRE |
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