Activation of PPARγ enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats

Abstract

It is suggested that insulin resistance and metabolic maladaptation of the heart are causes of contractile dysfunction. We tested the hypothesis whether systemic PPAR␥ activation, by changing the metabolic profile in a model of insulin resistance and type 2 diabetes (the ZDF rat) in vivo, improves contractile function of the heart in vitro. Male Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats, at 53-56 days of age, were treated with either GI-262570 (a nonthiazolidinedione PPAR␥ agonist; A) or vehicle (V) for 1 wk. Agonist treatment resulted in correction of hyperglycemia and dyslipidemia, as well as in reduced hyperinsulinemia. The accumulation of triacylglycerols in the myocardium, characteristic of the ZDF rat, disappeared with treatment. Cardiac power and rates of glucose oxidation in the isolated working heart were significantly reduced in ZDF-V rats, but both parameters increased to nondiabetic levels with agonist treatment. In ZDF-V hearts, transcript levels of PPAR␣-regulated genes and of myosin heavy chain-␤ were upregulated, whereas GLUT4 was downregulated compared with ZL. Agonist treatment of ZDF rats reduced PPAR␣-regulated genes and increased transcripts of GLUT4 and GLUT1. In conclusion, by changing the metabolic profile, reducing myocardial lipid accumulation, and promoting the downregulation of PPAR␣-regulated genes, PPAR␥ activation leads to an increased capacity of the myocardium to oxidize glucose and to a tighter coupling of oxidative metabolism and contraction in the setting of insulin resistance and type 2 diabetes.peroxisome proliferator-activated receptor-␥; Zucker diabetic fatty rat; diabetes mellitus; obesity; insulin; myocardial contraction; metabolism DIABETES MELLITUS ADVERSELY AFFECTS the cardiovascular system both at the level of the vasculature and at the level of the myocardium (45). Diabetes is considered an independent risk factor for heart failure (27), because abnormal ventricular function occurs in diabetic patients independently of clinically overt vascular disease (17, 32). Alterations in protein synthesis, calcium handling, and contractile proteins have all been implicated as key contributors to the development of cardiac dysfunction in diabetes (13,20). Changes in gene expression, energy substrate metabolism, and ultrastructure occur early in the course of the disease (45). Although the exact mechanism for the pathogenesis of diabetic cardiomyopathy is not understood, some of the first changes appear to be at the level of myocardial energy substrate metabolism (4, 36).Diabetes is as much a disease of dysregulated fatty acid metabolism as it is of dysregulated glucose metabolism (31). High rates of fatty acid uptake in the diabetic myocardium result in the accumulation of myocardial lipid and lipid intermediates, mitochondrial/peroxisomal generation of reactive oxygen species, and excessive oxygen consumption (18,50,52). These findings contrast with the metabolic characteristics of the normal heart.The normal heart readily adapts to changes in the environment by sw...

Rodent models of diabetic cardiomyopathy

“…Increased lipid peroxide levels, increased total superoxide dismutase activity, and the induction of antioxidant enzymes suggest that there may be oxidative stress in Zucker fatty rat hearts (Vincent et al, 2001;Conti et al, 2004). No change in SERCA2a mRNA expression has been observed in Zucker fatty rats Golfman et al, 2005).…”

“…The phenotype of the Zucker diabetic fatty rats (ZDF rats) originated from selective breeding of Zucker fatty rats that exhibited high glucose levels, thus ZDF rats are an inbred strain generated from the outbred Zucker fatty rat. ZDF rats are obese, hyperinsulinemic, hyperglycemic, hyperleptinemic and have consistently increased serum fatty acid and triglyceride levels (Clark et al, 1983;Golfman et al, 2005;Wang et al, 2005). ZDF rats are obese and insulin resistant until 6 weeks of age but, during this period, they are euglycemic.…”

“…Fractional shortening, as measured by echocardiography, is reduced in 20-week-old ZDF rats, and cardiac power, dP/dt and rate pressure product are all reduced in isolated perfused hearts of ZDF rats (Zhou et al, 2000;Sharma et al, 2004;Golfman et al, 2005;Wang et al, 2005). The hearts of ZDF rats develop hypertrophy and increased myocardial lipid storage (Zhou et al, 2000;Lee et al, 2001;Sharma et al, 2004;Golfman et al, 2005).…”

Potent Antidiabetic Effects of Rivoglitazone, a Novel Peroxisome Proliferator–Activated Receptor-γ Agonist, in Obese Diabetic Rodent Models

“…It has also been reported that the expression of GLUT4, a glucose transporter that plays a major role in insulin-dependent glucose uptake, was decreased and the expression of MCAD was increased in the hearts of ZDF rats compared with lean rats (32). Accordingly, the increased expression of GLUT4 and the decreased expression of ACO, CPT1b, and MCAD induced by rivoglitazone may contribute to improve cardiac metabolic abnormalities through promoting glucose utilization and reducing fatty acid β-oxidation in the hearts of ZDF rats.…”

“…Rivoglitazone had no effects on the expression levels of MHCs and SERCA2. It has been reported that GI-262570, a non-TZD PPARγ agonist, reduced the cardiac expression of ACO and PDK4 and that it improved cardiac contractile function with an increased rate of glucose oxidation in ZDF rats (32). Therefore, rivoglitazone may cause beneficial effects on cardiac function by modulating cardiac energy homeostasis.…”