Free fatty acid oxidation in insulin resistance and obesity

Abstract

The growing worldwide epidemic of obesity and diabetes portends a significant increase in cardiovascular disease. Obesity is associated with insulin resistance, and there is growing evidence that these conditions independently increase the risk of heart failure. Changes in myocardial substrate utilization develop in obesity and insulin resistance, and are characterized by increased fatty acid oxidation and utilization, and decreased glucose utilization. This paper will review the evidence for altered myocardial fatty acid utilization in obesity and insulin resistance, review mechanisms that are responsible, and discuss the relative contributions of systemic and myocardial insulin resistance in the regulation of fatty acid utilization in the heart.

Keywords: Fatty acid oxidation; insulin resistance; myocardial substrate utilization; obesity.

Figure 1

PPARa targets within cardiomyocytes. Activation of PPARa by increased availability of fatty acid ligands increases the expression of several genes (indicated by red stars) that mediate increased fatty acid uptake at the sarcolemma, increased generation of fatty acyl CoA, increased mitochondrial fatty acid uptake, and increased b-oxidation. ACO, acyl coenzyme A (CoA) oxidase; ACS, acyl CoA synthetase; CPT, carnitine palmitoyl transferase; FAT, fatty acid translocase; FABP, fatty acid binding protein; FATP, fatty acid transport protein; TCA, tricarboxylic acid; UCP, uncoupling proteins 2 and 3.

Figure 2

Mechanisms leading to increased myocardial fatty acid oxidation in insulin-resistant states. In the evolution of diet-induced obesity, or in type 2 diabetes, hyperinsulinemia activates insulin receptors (IR) and Akt (protein kinase B), leading to increased plasma membrane translocation of CD36, which leads to increased fatty acid uptake. Decreased expression and translocation of glucose transporter-4 (GLUT4) in insulin resistance leads to decreased glucose uptake and decreased glycolysis, which further increase fatty acid utilization. Reduced GLUT4 translocation precedes significant downregulation of insulin signal transduction to Akt. Mechanisms for reduced GLUT4 translocation are incompletely understood. Increased lipid availability activates PPARa, which leads to increased expression of proteins involved in fatty acid utilization, and increased pyruvate dehydrogenase kinase-4 (PDK4), which increase fatty acid oxidation (FAO) and decrease glucose oxidation, respectively. Increased FAO is associated with increased myocardial oxygen consumption (mVO₂). As insulin resistance progresses and diabetes ensues, reactive oxygen species (ROS)-mediated mitochondrial uncoupling develops, which further increases mVO₂, decreases ATP generation, and decreases cardiac efficiency. I–IV, Mitochondrial electron transport chain complexes I-IV; Akt-p, phospho-Akt/protein kinase B; ANT, adenine nucleotide translocase; CoA, coenzyme A; TAG, triacylglycerol; UCP, uncoupling proteins 2 and 3.