Abstract 654: Captopril Restores Insulin Sensitivity in ob/ob Mouse Hearts
Obesity is associated with cardiac insulin resistance and increased angiotensin 2 (Ang II) signaling, which inhibits insulin action in the heart. We sought to determine if chronic treatment with Captopril (CAP), an angiotensin converting enzyme inhibitor (ACEI) would increase myocardial insulin sensitivity in hearts of obese mice. Ob/ob and control mice were treated with CAP (4 mg/kg/day) or placebo for 4-weeks starting at weaning. Systemic AngII levels were increased in ob/ob mice (+ 25% vs controls, p<0.05) and were normalized by treatment with CAP. This was not associated with normalization of glucose tolerance tests or normalization of insulin levels in ob/ob mice. In isolated perfused working hearts, basal FA-OX and myocardial oxygen consumption (MVO2) were increased by 66% and 28% respectively in ob/ob mice (p<0.006) relative to controls. In control mice, insulin reduced FA-OX and myocardial oxygen consumption (MVO2) by 37% and 21% respectively (p<0.01), increased cardiac power by 25%, and glycolysis by 38% (p<0.01). In contrast, ob/ob mouse hearts were completely unresponsive to insulin indicating severe cardiac insulin resistance. CAP restored the ability of insulin to suppress FA-OX in ob/ob hearts from 292 ± 26 to 161 ± 18 nmol/min/g dwt (p<0.001) and the ability of insulin to reduce MVO2. Basal glycolytic rates were 50% lower in ob/ob mice vs controls but CAP significantly improved glycolysis in response to insulin stimulation (+50% vs non-treated ob/ob mice, p<0.01) and restored the inotropic effect of insulin (+ 21% vs non-treated ob/ob mice). Perfusion of control hearts with insulin increased Akt Thr308 phosphorylation by 2-fold (p<0.005) but was without effect in ob/ob hearts. CAP treatment completely restored insulin-stimulated Akt phosphorylation in ob/ob hearts. AMPK phosphorylation was higher in ob/ob mice vs controls (+ 2 fold vs controls, p<0.01) consistent with energetic stress, whereas CAP treatment returned phospho-AMPK to control levels. Taken together, these data show that although four weeks of treatment with therapeutic doses of Captopril did not improve whole body insulin sensitivity of obese ob/ob mice, it clearly restored insulin sensitivity in the heart as determined by an improvement in cardiac metabolism and function.