LONDON - The discovery of a protein that makes mice burn off fat and lose weight could eventually lead to a new generation of drugs to treat both obesity and Type II diabetes in one step.

The protein, known as uncoupling protein-3 (UCP-3), boosts energy expenditure when present at high levels in genetically manipulated mice. As a result, they have less body fat than normal, and gain less weight even when eating extra food. These mice are also more sensitive to insulin than wild type animals.

John Clapham, assistant director in the department of vascular biology at SmithKline Beecham Pharmaceuticals of Harlow, UK, told BioWorld International: "We have shown that UCP-3 is a viable target for the treatment of obesity. We are now going to look for agents that affect UCP-3, and take those forward as potential drug treatments for obesity. But even if we discovered one of those agents tomorrow, it would be at least 10 years' time before we had a drug on the pharmacy shelf."

Clapham described the discovery that mice with raised levels of UCP-3 show increased sensitivity to insulin as "exciting," given that many people who are obese also go on to develop Type II diabetes. These mice were able to clear glucose faster than their wild-type litter mates. "This means that we might be able to help people with insulin resistance by targeting the same protein," Clapham said.

The work is reported in a letter to the July 27 issue of Nature titled "Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean." The study was carried out in collaboration with researchers at the Medical Research Council's Dunn Human Nutrition Unit and the University of Cambridge, both in Cambridge, UK.

The uncoupling proteins play an important role in energy metabolism within the mitochondria of the cell. Energy taken into the body as food is normally coupled to processes that drive the vital functions of the body, such as respiration and movement. If energy is taken in excess of these needs, it is stored as fat. Alternatively, with the help of the uncoupling proteins, it can be burnt off without being coupled to the metabolic processes that consume energy.

During the past few years, several groups of researchers have been studying the uncoupling proteins. UCP-1 is found in brown adipose tissue, which has an important metabolic role in rodents, hibernating animals and human infants. A related protein, UCP-2, is found in many tissues in human beings.

Recently, a team at SmithKline Beecham, as well as several other groups, discovered a third uncoupling protein, UCP-3, which is predominantly expressed in skeletal muscle.

Clapham explained: "Because we knew that UCP-3 is related to UCP-1, which is involved in energy expenditure in rodents, and because skeletal muscle is responsible for 40 percent of basal metabolic rate in humans, this immediately raised our interest in this protein as a potential target for obesity."

He and his colleagues set out to prove that UCP-3 was indeed a viable drug target for obesity. They wanted to determine whether increasing the "dosage" of the protein would have an anti-obesity action.

A team at SmithKline Beecham in Harlow, led by Sohaila Rastan, director of the Comparative Genetics Group, went ahead by making transgenic mice which overexpress UCP-3 in skeletal muscle. So that they could distinguish between the gene which had been introduced and the one carried naturally by the animal, the gene introduced was the human version.

Tests showed that expression of UCP-3 from the human transgene was 66 times higher in skeletal muscle than would normally be expected. These animals weighed significantly less than wild type controls (p<0.05). Putting mice on a palatable diet increases food consumption and usually leads to weight gain. Although food consumption of the transgenic animals increased, they did not put on extra weight; instead, their weight tended to plateau at around the time they were put on the palatable diet.

Clapham and his colleagues inferred that UCP-3 exerted its fat-reducing effect by increasing resting metabolic rate, because the transgenic mice were no more active than the controls. Fat combustion is fuelled by oxygen, and resting oxygen consumption in the transgenic mice was 35 percent to 40 percent greater than in the controls.

With the help of collaborators from the Dunn Human Nutrition Unit, led by Martin Brand, the team determined that UCP-3 in mitochondria was having these effects by uncoupling energy metabolism. Magnetic resonance imaging of the animals showed that in the transgenic group there was a reduction in white adipose tissue. Males had a 44 percent decrease in the ratio of adipose tissue volume to the total volume of the animal, while this figure was 57 percent in females. Other data from the experiments showed that the cholesterol levels of the transgenic mice were 40 percent lower than those of controls. Their fasting glucose levels were lower, insulin levels were lower and glucose clearance rates were higher.

Clapham said, "Our conclusion is that yes, UCP-3 is a viable target for obesity research and now we need to discover drugs that affect it, either by increasing the activity of the protein, or by increasing the amount of protein that is expressed. So you can attack it from both ways."

The search is now on for agents that will have the desired effect, although Clapham emphasized that many more tests will need to be conducted before any new drugs could reach the market. He predicted that researchers would also want to determine the natural biological function of UCP-3. He added, "Moreover, further study of UCP-3 and its place in metabolic pathways may uncover still other novel approaches to therapy for obesity."

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