The impact of obesity and chronic PPAR Alpha agonist treatment on cardiac function, metabolism and ischaemic tolerance

[摘要] ENGLISH ABSTRACT:Background: Myocardial oxidative fuel supply is increased in obese conditions. Howthis metabolic environment and altered cardiometabolic phenotype associated with prediabeticobesity impacts on cardiac function and tolerance to ischaemia/reperfusioninjury remains uncertain. While obese individuals are likely to be treated with PPARαagonists, controversy exists as to how activation of the PPARα receptor influencescardiovascular function and post-ischaemic recovery. Aims: To determine in a model ofhyperphagia-induced obesity 1) whether protracted obesity is associated with leftventricular (LV) mechanical dysfunction; 2) the responsiveness of these hearts to insulinstimulation; 3) whether insulin can afford cardioprotection against ischaemia/reperfusiondamage; and 4) how obesity and chronic PPARα agonist (K-111) treatment influencesmyocardial function, substrate metabolism, mitochondrial function and post-ischaemicoutcomes.Methods: Male Wistar rats were fed standard rat chow or a high caloric diet. 1) In vivoLV mechanical function was assessed echocardiographically in 32 week fed animals. Exvivo LV function was measured in the presence of glucose, insulin and/or fatty acid (FA);2) Ex vivo myocardial insulin sensitivity was assessed by measuring insulin stimulatedglycolytic flux in 16 week fed rats. Insulin was also administered prior to and duringregional ischaemia to determine its effect on post-ischaemic function and infarct size; 3)K-111 was added to the drinking water during the last 10 weeks of feeding (feedingperiod of 18 weeks); a) Ventricular mitochondrial function was determinedpolarographically in the presence of either glutamate or palmitoyl-L-carnitine assubstrates; b) Myocardial carbohydrate and lipid metabolism, and in a separate series of perfusions, myocardial infarct size were determined in the presence of physiological orhigh insulin (30 or 50μIU/ml) and FA (0.7 or 1.5mM) concentrations.Results: 1) Obese animals maintained normal in vivo LV mechanical function. Glucoseperfused hearts from obese animals had depressed aortic outputs compared to thecontrol group (32.58±1.2 vs. 46.17±0.91 ml/min; p<0.001) which was abolished by thepresence of FA; 2) Hearts from obese animals had reduced insulin stimulated glycolyticflux rates (1.54±0.42 vs. 2.16±0.57 μmol/g ww/min, p<0.01). Although insulin reducedinfarct size in the obese group (20.94±1.60 vs. 41.67±2.09 %, p<0.001), itscardioprotective effect was attenuated in the presence of FA; 3) By simulating the in vivometabolic environment of control and obese animals in ex vivo perfusions, elevatedinsulin and FA levels associated with obesity increased infarct sizes in the obese groupcompared to the control group (47.44±3.13 vs. 37.17±2.63 %, p<0.05); 4) While chronicK-111 treatment reversed systemic metabolic abnormalities associated with obesity,neither obesity nor the drug influenced myocardial and mitochondrial function or postischaemicoutcomes. K-111 was able to reduce palmitate oxidation in the obese group.Conclusion: Elevated levels of circulating FFA may be important in maintaining normalLV mechanical function in the obese condition. While obesity had no impact onmyocardial mitochondrial function and post-ischaemic outcomes during comparableperfusion conditions, the specific metabolic environment associated with obesity mayaugment post-ischaemic injury. K-111 is effective in reducing obesity related metabolicabnormalities, but has no effects on myocardial function, mitochondrial function orischaemic tolerance.

[发布机构] Stellenbosch University