The impact of fatty acid oxidation on energy utilization: targets and therapy.

Utilization of fat as a long-term energy storage vehicle is crucial for the maintenance of cellular metabolism and is under intricate and many times redundant control mechanisms. Aberrations in the control of energy metabolism is apparent in diseases such as diabetes and obesity and is evident early on in patients with impaired glucose tolerance. Insulin resistance has been observed at the level of muscle, liver and adipose tissue. Hyperglycemia is the hallmark of diabetes and is characterized by decreased glucose disposal and increased glucose production, driven by enhanced and uncontrolled fatty acid oxidation (FAO). Mechanisms aimed at limiting the availability of substrates or the activity of processes involved in FAO should provide an immediate reduction in undesired glucose production in these individuals. Numerous targets are available which influence directly the metabolism of fat, including limiting availability of substrate to FAO, inhibiting oxidation of the fatty acid per se, and uncoupling the energy obtained during the oxidation of the fatty acid. These include antilipolytic agents which limit the availability of substrate, FAO inhibitors which limit fatty acid transport (carnitine palmitoyl transferase, CoA sequestration), FAO per se (beta oxidation), and agents which uncouple the energy of FAO (uncoupling proteins, beta3 agonists). These other targets which affect fatty acid metabolism indirectly will be discussed in this review with 184 references.