By Gila Reckess
School of Medicine research- ers have developed geneti- cally-altered mice that do not become obese or develop diabetes when fed a high-fat diet. This work suggests that it is possible to alter muscle metabolism and body weight in animals by producing this protein in muscle.
"We've produced mice that can eat as much as they like without suffering the consequences of obesity and diabetes," said Clay F. Semenkovich, M.D., professor of medicine and of cell biology and physiology.
 Clay F. Semenkovich, M.D., professor of medicine, and Lorraine A. Nolte, Ph.D., research assistant professor of medicine, show off their study's results. They used genetic techniques to produce a protein in the skeletal muscle of the mouse on the right that enabled it to eat a high-fat diet and not become fat. This work suggests it is possible to alter muscle metabolism and body weight in animals. |
Semenkovich directed the study, which is reported in the October issue of Nature Medicine. Bing Li, M.D., Ph.D., postdoctoral research fellow, and Lorraine A. Nolte, Ph.D., research assistant professor of medicine, are first authors of the paper. The study was conducted in collaboration with John O. Holloszy, M.D., professor of medicine.
The food you eat normally generates ATP, a form of chemical energy used by cells. That energy powers your muscles during exercise. But without exercise, ATP is used to make and store fat. This strategy was useful during times of famine, but now it sets the stage for dangerous levels of obesity in Western society, where food is plentiful and exercise is scarce. And obesity often causes insulin resistance, which can lead to diabetes.
Semenkovich and colleagues used genetic techniques to produce a protein called uncoupling protein-1 in the skeletal muscle of laboratory mice. This proteinconverts the energy from food into heat instead of into ATP. The protein, however, is not normally produced in skeletal tissue. The production of uncoupling protein in muscle tissue mimicked the effects of exercise. Rather than storing excess fat from their consistently bad diet, the experimental mice remained thin, did not develop diabetes and had low levels of cholesterol. But almost all of their littermates became obese, developed diabetes and had high levels of cholesterol when they ate the high-fat diet.
Remarkably, the treated mice did not overheat, either. Somehow, the uncoupling protein used up the excess energy without raising body temperature. The animals also were as physically fit as mice that ate a low-fat diet. They had the same levels of high-energy phosphates, such as ATP and phosphocreatine, in their muscle. And they could run on a treadmill at 5 miles per hour.
"Uncoupling protein may be a replacement for exercise," Semenkovich explained. "It burns fuel in muscle, which provides the same key benefits." For example, the protein makes more glucose flow into muscle tissue. By regulating glucose metabolism, it prevents mice from developing diabetes.
In the future, a similar treatment might permit humans to stay healthy and slim despite poor eating habits. First, however, an effective and safe means of introducing the protein into human muscle would have to be developed.
In the near term, the researchers hope to determine whether gene therapy can reverse obesity and diabetes in already diseased animals. This strategy, too, has the potential eventually to help humans.
"It may be possible, either through drugs or gene therapy, to turn on something like uncoupling protein that would waste energy instead of storing it in fat," Semenkovich said. "Such treatments would promote leanness."
