Pioglitazone reverses down-regulation of cardiac PPARγ expression in Zucker diabetic fatty rats

doi:10.1016/j.bbrc.2005.02.029

Biochemical and Biophysical Research Communications

Volume 329, Issue 2, 8 April 2005, Pages 726-732

https://doi.org/10.1016/j.bbrc.2005.02.029 Get rights and content

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) plays a critical role in peripheral glucose homeostasis and energy metabolism, and inhibits cardiac hypertrophy in non-diabetic animal models. The functional role of PPARγ in the diabetic heart, however, is not fully understood. Therefore, we analyzed cardiac gene expression, metabolic control, and cardiac glucose uptake in male Zucker diabetic fatty rats (ZDF fa/fa) and lean ZDF rats (+/+) treated with the high affinity PPARγ agonist pioglitazone or placebo from 12 to 24 weeks of age. Hyperglycemia, hyperinsulinemia, and hypertriglyceridemia as well as lower cardiac PPARγ, glucose transporter-4 and α-myosin heavy chain expression levels were detected in diabetic ZDF rats compared to lean animals. Pioglitazone increased body weight and improved metabolic control, cardiac PPARγ, glut-4, and α-MHC expression levels in diabetic ZDF rats. Cardiac [¹⁸F]fluorodeoxyglucose uptake was not detectable by micro-PET studies in untreated and pioglitazone treated ZDF fa/fa rats but was observed after administration of insulin to pioglitazone treated ZDF fa/fa rats. PPARγ agonists favorably affect cardiac gene expression in type-2 diabetic rats via activation and up-regulation of cardiac PPARγ expression whereas improvement of impaired cardiac glucose uptake in advanced type-2 diabetes requires co-administration of insulin.

Section snippets

Materials and methods

Animal models and treatment. Male obese zucker diabetic fatty rats (ZDF, fa/fa) and age matched lean control animals (ZDF lean, fa/+ or +/+) were purchased from Charles River laboratories at 10 weeks of age and marked individually by ear tags. Pioglitazone powder was obtained from Takeda Pharmaceuticals. Animals were randomized according to genotype in four groups (ZDF fa/fa pio; ZDF fa/fa placebo; ZDF lean pio; ZDF lean placebo; n = 10/group) at 12 weeks of age and treated for 12 weeks either

Global and metabolic parameters

Fasting serum glucose levels were significantly higher in diabetic ZDF fa/fa rats compared to lean animals and lowered by pioglitazone treatment in ZDF fa/fa but not in normoglycemic lean rats. Plasma insulin levels were higher in ZDF fa/fa rats treated with pioglitazone or placebo compared to lean controls. Serum triglyceride levels, which were elevated in diabetic compared to lean ZDF rats, were decreased in pioglitazone treated diabetic ZDF rats. Body weight was not different between all

Discussion

The present study shows that activation of PPARγ by pioglitazone significantly improves impaired cardiac PPARγ, glut-4, and α-MHC expression levels in type-2 diabetic rats. Cardiac [¹⁸F]FDG uptake, which was below detection limits in diabetic ZDF fa/fa rats, increased significantly only upon co-administration of pioglitazone and insulin. These findings support the hypothesis that activation of PPARγ confers favorable effects on cardiac gene expression in type-2 diabetic hearts and that insulin

Acknowledgments

This study was supported in part by grants from the IZKF Würzburg (T. Pelzer), the German Academic Exchange Service “DAAD” (V. Jazbutyte and P. Arias-Loza), and the IZKF Münster (ZPG4, M. Schäfers, and M.P. Law). The authors thank Mrs. Christine Bätza for assistance with PET scanning.

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Pioglitazone reverses down-regulation of cardiac PPARγ expression in Zucker diabetic fatty rats

Abstract

Section snippets

Materials and methods

Global and metabolic parameters

Discussion

Acknowledgments

J. Am. Coll. Cardiol.

J. Biol. Chem.

Cell

Trends Pharmacol. Sci.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Mechanisms determining course and outcome of diabetic patients who have had acute myocardial infarction

Ann. Intern. Med.

Metabolic syndrome and hypertension: pathophysiology and molecular basis of insulin resistance

Basic Res. Cardiol.

Diabetic cardiomyopathy

Cardiovasc. Drugs Ther.

Cardiac dysfunction in the Goto-Kakizaki rat. A model of type II diabetes mellitus

Basic Res. Cardiol.

Peroxisome proliferator-activated receptors, orphans with ligands and functions

Curr. Opin. Lipidol.