Oct. 3, 2000 St. Louis, Oct. 1, 2000 – Researchers have developed genetically-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," says Clay Semenkovich, M.D., professor of medicine and of cell biology and physiology at Washington University School of Medicine in St. Louis.
Semenkovich directed the study, which is reported in the October issue of Nature Medicine. Both 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 it now 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 protein converts 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 mph.
In the future, a similar treatment may permit humans to stay healthy and slim despite poor eating habits. First, an effective and safe means of introducing the protein into human muscle would have to be developed.
"Uncoupling protein may be a replacement for exercise," explains Semenkovich. "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 near future, the researchers hope to determine whether gene therapy can reverse obesity and diabetes in already diseased animals. This strategy has the potential to eventually 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 says. "Such treatments would promote leanness."
Li B, Nolte LA, Ju JS, Han DH, Coleman T, Holloszy JO, Semenkovich CF. Skeletal Muscle Respiratory Uncoupling Prevents Diet-Induced Obesity and Insulin Resistance In Mice. Nature Medicine, Oct., 2000.
This work is supported by the National Institute of Diabetes, Digestive and Kidney Diseases, the National Heart, Lung and Blood Institute and the National Institute on Aging.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health System.
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