Abstract 509: Myocardial Fatty Acid Oxidation Rates Remain Elevated in ob/ob Mice Despite Reversal of Obesity and Diabetes by Caloric Restriction
Leptin deficient ob/ob mice are commonly used to study the effects of obesity and insulin resistance on myocardial substrate metabolism. However, it is difficult to discern the specific contribution of obesity, insulin resistance and diabetes versus leptin deficiency to the observed phenotypes. We therefore adopted a strategy using caloric restriction to normalize body weight and reverse insulin resistance to study the effect of leptin deficiency on myocardial metabolism in lean ob/ob mice. Male 4-week old ob/ob mice were “pair fed” to a leptin-treated group (3mg/kg/day by i.p. injection) for three weeks. Glucose tolerance, serum insulin, serum triglycerides and FA oxidation rates in hearts perfused with 0.4mM palmitate ± 1 nM insulin were determined. Leptin-treated ob/ob mice ate significantly less than non-treated ob/ob mice, and their weight returned to wild type levels. Hyperglycemia, hyperinsulinemia, hypertriglyceridemia and cardiac hypertrophy were also completely reversed in leptin-treated ob/ob mice. In contrast, cardiac hypertrophy persisted in pair fed ob/ob mice and despite normalization of glucose tolerance and insulin levels, serum triglyceride concentrations increased by 2 and 6 -fold in pair fed ob/ob mice relative to untreated ob/ob and wildtype mice respectively (p<0.05). As previously reported, palmitate oxidation rates were 2.1-fold increased in ob/ob hearts relative to controls (p<0.005) and were normalized with leptin treatment. In contrast, palmitate oxidation rates remained elevated in pair fed ob/ob mice relative to wildtype controls (1.9-fold, p<0.01). Insulin has a positive inotropic effect in perfused wildtype hearts, and this effect was absent in ob/ob hearts. The insulin-induced inotropic response was restored by leptin treatment in ob/ob mice but was not restored in pair fed ob/ob mice. These data support a direct antihypertrophic effect of leptin in the heart and suggest that leptin deficiency may directly contribute to myocardial insulin resistance and abnormal FA metabolism. Potential mechanisms include increased hepatic triglyceride production in leptin deficiency or direct effects of leptin signaling in the hypothalamus and/or the periphery on myocardial substrate utilization.