Abstract 1126: Differential Effects of High-Fat Feeding on the Ability of Insulin to Modulate Glucose versus FA Utilization in the Heart
High fat feeding (HFD) induces insulin resistance in multiple tissues including the heart. We evaluated the effect of HFD on the ability of insulin to modulate myocardial substrate metabolism in 10-week-old C57BL6 mice fed a HFD (45% fat) for two and five weeks. Substrate metabolism was determined in isolated working hearts in the presence or absence of 1 nM insulin. HFD led to decreased basal rates of glycolysis and glucose oxidation and increased basal rates of FA oxidation (FAO) and MVO2 at 2 and 5-weeks (see table⇓). Insulin’s ability to stimulate glycolysis was completely lost as early as 2-weeks of HFD and insulin stimulated glucose oxidation was attenuated. In contrast, the ability of insulin to inhibit FA oxidation was maintained in HFD hearts. To determine if changes in mitochondrial energetics could account for observed changes in whole heart metabolism we examined mitochondrial oxygen consumption and ATP production in saponin-permeabilized cardiac fibers exposed to 5 mM glutamate with 2 mM malate, 10 mM pyruvate with 5 mM malate, 5 mM succinate with 5 μM rotenone, or 20 μM palmitoyl-l-carnitine with 5 mM malate. After two and five weeks, there was no significant change in oxygen consumption, ATP production or ATP/O ratios in HFD mitochondria. However, the activity of malonyl-CoA decarboxylase that degrades malonyl-CoA was increased in HFD hearts as early as 2 weeks of HFD (3.72 ± 0.15 vs. 3.18 ± 0.20 nM/min/μg protein in control hearts, p=0.05). Thus HFD rapidly alters myocardial metabolism and selectively impairs the ability of insulin to modulate glucose but not FA utilization. Increased mitochondrial uncoupling is not directly responsible for changes in FA metabolism in response to HFD, but allosteric mechanisms that regulate malonyl CoA levels and CPT-1 activity are responsible for increasing FAO and MVO2.