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STUDY OF FAT-REDUCING PROTEIN OPENS NEW PATH TOWARD OBESITY TREATMENT Report in Nature from SmithKline Beecham, the Medical Research Council Dunn Human Nutrition Unit and University ofUniversity Cambridge Details Results of Enhancing "Lean Gene" Effect Philadelphia, PA, July 26, 2000 -- In work that opens a new investigative path toward treatment of obesity, scientists have found in animal studies that artificially high levels of a protein that regulates metabolism markedly reduces fat deposition even as food consumption increases, it is reported in the current issue of Nature1. The protein, known as Uncoupling Protein 3 (UCP3), is a recently discovered member of a group of proteins involved in energy metabolism within intracellular organelles known as mitochondria, the engine rooms of the cell. It is through this metabolism that energy taken into the body as food is coupled to processes that drive the vital functions of the body. Excess energy is stored as fat, unless it can be burnt off without being coupled to these processes. Uncoupling is rather like depressing both the accelerator and clutch in a car, so that fuel is burnt without producing movement. As reported in Nature, researchers at SmithKline Beecham studied the effects of UCP3 in mice that had been genetically altered so as to produce artificially high levels of this uncoupling protein. Specifically, expression of the gene holding the cellular production code for the protein was enhanced in skeletal muscle: This lean gene, as it might be thought of, was made to work overtime, and so the cell's protein-making machinery produced more UCP3. Colleagues at the MRC Dunn Human Nutrition Unit and University of Cambridge determined that UCP3 in the mitochondrial fraction was acting to uncouple energy metabolism. As reported in Nature, the altered, or transgenic, mice exhibited a striking 44-57% reduction of fat-tissue mass in comparison with the unaltered mice. What was more, the reduction of fat in the transgenic mice was observed even though they surprisingly consumed 15-54% more food energy than the unaltered controls. Since the transgenic mice were no more active than the controls, the researchers inferred that UCP3 exerted its fat-reducing effect by increasing resting metabolic rate. Supporting this inference was the observation that resting oxygen consumption in the transgenic mice was 35-40% greater than in the controls. Fat combustion is fueled by oxygen. "Given all the data available to us today, we now believe that stimulating UCP3 activity is a promising approach to obesity therapy," said Dr. John Clapham, assistant director, Vascular Biology, SB. "Moreover, further study of UCP3 and its place in metabolic pathways may uncover still other novel approaches to therapy." Still, Dr. Clapham cautioned, "The precise metabolic role played by UCP3 remains unclear, and many more studies remain to be done before this line of research might result in new obesity drugs." The direct evidence provided by this latest study for a role of UCP3 in energy consumption is consistent with indirect evidence from previous studies. This latest study also indicated that, aside from fat combustion, UCP3 at high levels also produced other effects of interest for drug discovery: The transgenic mice exhibited 70% lower cholesterol levels than those of the controls, lower fasting glucose levels and lower insulin levels, and increased glucose clearance rates. The work reported in Nature supplements other research efforts at SB in obesity. Last year, Nature carried a report from SB identifying the cell-surface receptor for melanin-concentrating hormone, a hormone involved in regulation of appetite. That discovery followed the identification by SB scientists and their academic collaborators of orexins and their receptors, hormone-receptor pairs first associated with appetite and, more recently, a sleeping disorder called narcolepsy. The report also offers another example of the usefulness of transgenic mice in research intended to yield new therapies. By modifying the gene that encodes a protein of interest, in this instance the gene encoding UCP3, researchers can better study the role of that protein in health and disease. The team conducting the UCP3 work for SB was based in Harlow, England, and led by Dr. John Clapham. The transgenic team was led by Dr Sohaila Rastan. The team at the MRC Dunn Human Nutrition Unit and University of Cambridge, England, was led by Martin Brand. SmithKline Beecham (NYSE:SBH)—one of the world's leading healthcare companies—discovers develops, manufactures, and markets pharmaceuticals, over-the-counter medicines, and health-related consumer products. For company information, visit SmithKline Beecham on the World Wide Web at http://www.sb.com. |
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