Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean

Uncoupling protein-3 (UCP-3) is a recently identified member of the mitocho ndrial transporter superfamily(1,2) that is expressed predominantly in skel etal muscle(1,2). However, its close relative UCP-1 is expressed exclusivel y in brown adipose tissue, a tissue whose main function is fat combustion a nd thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy ba lance and lipid metabolism(3,4). However, direct evidence for these roles i s lacking. Here we describe the creation of transgenic mice that overexpres s human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a strik ing reduction in adipose tissue mass. The mice also exhibit lower fasting p lasma glucose and insulin levels and an increased glucose clearance rate. T his provides evidence that skeletal muscle UCP-3 has the potential to influ ence metabolic rate and glucose homeostasis in the whole animal.