Energy contained in the food we eat is preserved in the chemical potential of adenosine triphosphate (ATP) after carbohydrates, lipids, and proteins are oxidized to carbon dioxide and water. Oxidation takes place inside mitochondria, and the energy of electron transfer through the electron-transport chain is maintained by extrusion of protons from the matrix, producing an electrochemical gradient across the inner mitochondrial membrane. Dissipation of the protein gradient through the F1 ATPase complex of the inner membrane then leads to ATP synthesis.
It has long been known that brown adipose tissue has a high capacity for heat production, because the mitochondria of this tissue contains a protein called uncoupling protein (UCP1), which dissipates the proton gradient through the inner membrane, with the energy being released as heat instead of ATP synthesis. Since obesity is associated with energy imbalance, it was speculated that more uncoupling protein might protect against obesity. Evidence to support this hypothesis was provided by an experiment in which UCP1 was overexpressed in skeletal muscle. The UCP1 overexpressing transgenic mice were resistant to weight gain and obesity when placed on a high-fat diet.66 However, since UCP1 is normally only found in brown adipose tissue, and humans have little or no brown adipose tissue, the significance of UCP1 in human obesity is questionable.
After the cloning of two proteins with high homology to UCP1 (UCP2 and UCP3), there was renewed interest in whether uncoupling proteins might be a factor in obesity. Both UCP2 and UCP3 were confirmed to cause uncoupling of oxidative phosphorylation. UCP2 is ubiquitously expressed, while UCP3 is primarily expressed, in muscle. UCP2 and UCP3 have been extensively studied, but there is no clear link between these uncoupling proteins and obesity.44
The physiological function of uncoupling proteins is somewhat puzzling. UCP3 expression is paradoxically increased by fasting and acute exercise, but these responses are secondary to the release of fatty acids, which are potent regulators of UCP3 transcription. Thus, there seems to be a link between lipid metabolism and the expression of UCP3 in muscle.95 Since altered lipid metabolism is related to insulin resistance (see later sections of this chapter), uncoupling proteins may play an indirect role in the changes in metabolism seen in obesity.
In addition to producing ATP, mitochondria are also a major source of reactive-oxygen species, which can cause DNA damage and peroxidation of membrane lipids. Recent evidence suggests that one of the functions of uncoupling proteins in muscle may be to prevent the proton gradient across the inner mitochondrial membrane from becoming too high, which would lead to the production of harmful reactive-oxygen species.4095 Damage to mitochondrial membranes and mitochondrial DNA by reactive-oxygen species may be responsible for the defects that have been observed in muscle mitochondria of diabetic and aged individuals.57,80 In fact, impaired mitochondrial activity may play a much larger role in disease than previously recognized, since insulin-resistant offspring of patients with type 2 diabetes were also recently found to have reduced capacity for oxidative phosphorylation.81
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