PPARγ agonist induced cardiac enlargement is associated with reduced fatty acid and increased glucose utilization in myocardium of Wistar rats
Introduction
Thiazolidinediones are used clinically to improve blood glucose control in patients with type-2 diabetes, and are potent agonists of peroxisome proliferator-activated receptor-gamma (PPARγ). PPARγ agonists may be useful also for correcting other metabolic disturbances such as the dyslipidemia associated with the metabolic syndrome. Disturbances in fuel metabolism, especially lipid oversupply to the heart, may also be responsible for the so called diabetic cardiomyopathy (Zhou et al., 2000) and there is evidence that PPARγ agonists could play an important role in the correction of these disturbances (Berthiaume et al., 2004, Minoura et al., 2004, Oakes et al., 2001, Pickavance et al., 1999).
Numerous studies have documented the beneficial metabolic effects of PPARγ activation in animal models of the metabolic syndrome (Golfman et al., 2005, Zhou et al., 2000), including correction of hyperglycaemia and hypertriglyceridemia. Very little information is available in published form about findings in toxicological studies where high doses of PPARγ agonists are given to healthy animals. It has been shown that in this situation PPARγ agonists induce cardiac enlargement, increase plasma volume (Arakawa et al., 2004, Pickavance et al., 1999) and dramatically reduce plasma triglyceride concentration without causing hypoglycaemia (Berthiaume et al., 2004, Minoura et al., 2004). The eccentric cardiac enlargement induced in normal animals is accompanied with an increased left ventricular end diastolic pressure and has been considered a consequence of the increased plasma volume, leading to cardiac volume overload (Arakawa et al., 2004), rather than a direct hypertrophic effect on the cardiomyocytes (Bell and McDermott, 2005).
We here hypothesize that in the normal animal, high doses of PPARγ agonists induce cardiac enlargement via extreme alterations in cardiac fuel metabolism caused by the ability of these agents to lower lipid availability. There are several situations where disturbances in fatty acid fuel metabolism are associated with cardiac enlargement and sometimes even cardiomyopathy. These include administration of fatty acid oxidation inhibitors (Litwin et al., 1990); fatty acid-free diets (Panos and Finerty, 1954); chronic insulin/glucose infusions (Belke et al., 2002, Holmang et al., 1996); genetic defects in oxidative metabolism (for review see (Antozzi and Zeviani, 1997, Eaton et al., 1996, Russell et al., 2005); and modulation of cardiac enzymes involved in oxidation (Sack et al., 1996, Schiffrin, 2005).
We have previously shown that PPARγ agonism ameliorated the ‘lipid overload’ condition in obese, dyslipidemic rats given therapeutic doses by: 1) increasing the ability of the adipose tissue to take up and store plasma free fatty acid, 2) enhancing insulin-mediated suppression of systemic free fatty acid mobilization, and 3) lowering hepatic triglyceride production and augmenting plasma triglyceride clearance (Oakes et al., 2001). No comparable information is available on the effect of these agents in healthy animals. This is especially important since the heart is thought to be highly dependant on circulating lipids (free fatty acid and triglyceride) for oxidative fuel metabolism. Thus induction of a severe hypolipidemia in metabolically healthy animals may seriously challenge normal cardiac energy metabolism and manifest itself much like the clinical situations of some inborn errors of metabolism. Therefore, the same pharmacologic effect (lipid lowering) could have very different consequences in healthy animals given high doses compared to animal models with the metabolic syndrome given therapeutic doses.
The aims of the present study were to document effects of intense PPARγ stimulation on in vivo cardiac fuel utilization and to investigate whether alterations in metabolism contribute to the cardiac enlargement in normal animals. For this purpose we studied the effects of a novel potent PPARγ agonist (X334) in Wistar rats, on cardiac free fatty acid and glucose uptake in vivo, circulating lipid availability, ventricular weight and plasma volume. The compound X334 induced profound hypolipidemia and to investigate whether this contributed to the observed cardiac enlargement we attempted to restore lipid availability using various interventions in combination with PPARγ treatment.
Section snippets
Animals and general procedures
Experimental procedures were approved by the Local Ethics Review Committee on Animal Experiments (Gothenburg Region, Sweden) and complied with the European Community guidelines for the use of experimental animals. Male Wistar rats (M and B Taconic, Ry, Denmark) were individually housed in a temperature (20–22 °C) and humidity (40–70%) controlled facility with a 12-h light/dark cycle (lights on 6:00 am). Unless otherwise stated the animals had free access to standard rodent diet (R3; Laktamin
Cardiac hypertrophy and hypolipidemia induced by high dose PPARγ agonist treatment in normal rats
Summary data describing the effect of two-week treatment of Wistar rats with the potent PPARγ agonist X334 on body weight, ventricular (left and right) weight and plasma clinical chemistry are presented in Table 1. Compared to vehicle treated animals, the groups X334 (3 μmol/kg/d) and X334 (10 μmol/kg/d) decreased plasma triglyceride concentration 61% and 69% respectively, and decreased plasma free fatty acid levels 72% and 62% respectively. PPARγ activation resulted in a significant increase
Discussion
We observed that intense PPARγ activation for two weeks in metabolically healthy Wistar rats with the potent and selective PPARγ agonist X334, induced cardiac enlargement, as evidenced by increased cardiac mass resulting from an eccentric cardiac hypertrophy. This enlargement was greater than that which could be explained by the increase in body-weight gain which results from increased food consumption, a well known effect of PPARγ agonism, (Berthiaume et al., 2004, Larsen et al., 2003,
Acknowledgments
The authors would gratefully like to acknowledge Lennart Svensson and his group for performing the biochemical analyses. We are also grateful to Ulrika Lindahl for help with the food restriction study. Amanda Edgley was supported by a National Health and Medical Research Council of Australia Industry Fellowship (Grant # 237003).
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