Abstract
Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on fatty acids for energy production.
Highlights
70% of the ATP produced in the heart is derived from the oxidation of fatty acids
The heart does, increase the utilization of glucose in response to enhanced availability, increased workload, and physiologic and pathophysiological stress. This metabolic flexibility is essential for cardiac function because: 1) Glucose relative to fatty acids produces more ATP per molecule of oxygen consumed and 2) Glycolytic intermediates are required for processes other than ATP production [1]
Mitochondria isolated from mice on the high fat diet (20 wk) exhibited a ~40% reduction in state 3 respiration relative to mitochondria from control animals (Figure 1A and Table 1)
Summary
70% of the ATP produced in the heart is derived from the oxidation of fatty acids. The heart does, increase the utilization of glucose in response to enhanced availability, increased workload, and physiologic and pathophysiological stress. This metabolic flexibility is essential for cardiac function because: 1) Glucose relative to fatty acids produces more ATP per molecule of oxygen consumed and 2) Glycolytic intermediates are required for processes other than ATP production [1]. It is noteworthy that obesity and diabetes result in diminished cardiac glucose oxidation and a heavy reliance on β-oxidation for energy production [2,3]. A diet rich in fat promotes diminished cardiac glucose utilization prior to overt manifestations of obesity, diabetes, and cardiac dysfunction [6,7]. Identifying early events and mechanisms that contribute to diet-induced metabolic inflexibility may offer promise for therapeutic intervention that reestablish proper metabolic balance
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