Myocardial substrate metabolism in obesity

Abstract

Obesity is linked to a wide variety of cardiac changes, from subclinical diastolic dysfunction to end-stage systolic heart failure. Obesity causes changes in cardiac metabolism, which make ATP production and utilization less efficient, producing functional consequences that are linked to the increased rate of heart failure in this population. As a result of the increases in circulating fatty acids and insulin resistance that accompanies excess fat storage, several of the proteins and genes that are responsible for fatty acid uptake and metabolism are upregulated, and the metabolic machinery responsible for glucose utilization and oxidation are inhibited. The resultant increase in fatty acid metabolism, and the inherent alterations in the proteins of the electron transport chain used to create the gradient needed to drive mitochondrial ATP production, results in a decrease in efficiency of cardiac work and a relative increase in oxygen usage. These changes in cardiac mitochondrial metabolism are potential therapeutic targets for the treatment and prevention of obesity-related heart failure. (2013) Keywords: myocardial metabolism; review; obese INTRODUCTION Cardiac energy metabolism is essentially a four-step process involving the following: (1) myocellular substrate uptake/selection, (2) mitochondrial ATP production and (3) ATP transfer from the site of production (mitochondrion) to (4) the site of ATP utilization (cardiac myofibril; Figure 1). 1 Although glycolysis is an ATP generator, the overall ATP production is controlled largely by the rate at which the Krebs (tricarboxylic acid) cycle operates. 2 Acetyl co-enzyme A (CoA), which is produced from the oxidation of fatty acids, ketone bodies, or glucose via glycolysis, and the pyruvate dehydrogenase (PDH) enzyme complex 3 enters the Krebs cycle for complete oxidation. During oxidative phosphorylation, electrons, primarily obtained from oxidative metabolism of carbohydrates and fats, are transferred through the electron transport chain, a fourcomplex protein system embedded within the inner membrane of the mitochondria. The major function of the electron transport chain is to produce a proton electrochemical potential difference between two compartments that powers ATP synthase to generate ATP, which is used for all cardiac cellular processes. 4 ATP is the heart's only immediate source of energy for contraction, and as both systole and diastole are ATP-consuming processes, 5,6 cardiac ATP demand is very high. To keep up with this demand for continuous and efficient contraction and relaxation, the heart needs to produce around 20 times its own weight in ATP per day. 1 As a result of this large energy requirement, any impairment in ATP production, transfer or utilization can have detrimental effects on cardiac function. 7 Cardiac metabolism and ATP production is altered in obesity and has emerged as a candidate mechanism to explain the increase in heart failure in this population. 8 Indeed, it has recently been shown that obesity, in the absence of co-morbiditie...

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