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Muscle of obese 'programmed' to amass fat, genetic study finds

Cell Press

The skeletal muscle of severely obese people is "programmed" to amass fat, a study in the October 2005 issue of Cell Metabolism reveals. The findings suggest that muscle bears a metabolic memory of obesity, which may help to explain why sustained weight loss can be difficult despite cutting calories, according to the researchers. Exercise might more successfully override the aberrant metabolic program in muscle, they suggest, thereby improving the long-term prognosis of those prone to obesity.

A diverse team of researchers found that the fat-building enzyme stearoyl-CoA desaturase-1 (SCD-1) is three times more abundant in muscle taken from obese people than in muscle from those who are lean. The newly discovered elevation in enzyme activity elucidates an important link between obesity, diabetes, and abnormal fat buildup in muscle, said study author Deborah Muoio of the Sarah W. Stedman Nutrition and Metabolism Center at Duke University Medical Center.

"Obesity and type 2 diabetes are strongly associated with abnormal lipid metabolism and the accumulation of fat droplets in muscle, but the underlying causes of these perturbations have been unknown," Muoio said. "We've now shown that SCD1 is at least a very important contributor to changes in lipid handling within muscle and the progression of obesity."

The researchers examined muscle removed from lean and obese patients during surgery. An earlier study had found that the obese individuals, while not diabetic, did show severe insulin resistance. The muscle of those individuals was laced with fat droplets, they found, and also showed a 43% decline in the ability to burn fat.

Results of a comprehensive profile of gene activity showed a link between obesity and a 3-fold increase in muscle SCD1 levels. That increase in enzyme expression and activity also corresponded with diminished fat burning and changes in the fat composition of muscle. In contrast, many other genes with known roles in fat production did not differ between obese and lean people, they reported.

The differences between muscles of lean and obese donors persisted in primary myocytes--cells poised to differentiate into muscle tissue. Muscle cells from lean individuals, when forced to over-produce SCD1, also took on characteristics that mimicked those seen in the cells of obese people.

The findings suggest that the muscular abnormalities seen in obese individuals stemmed from an inherited genetic predisposition or from imprinted defects in metabolic genes, Muoio said. Imprinting, or epigenetics, refers to permanent or semipermanent modification in gene activity states not conferred by changes in the underlying DNA sequence.

"Compelling evidence indicates that deviant nutrition during critical developmental periods can impose imprinted metabolic adaptations that persist into adulthood," the researchers wrote. "Such observations suggest that transient environmental stress can trigger permanent alterations in metabolic control. Thus, our findings could reflect an epigenetic phenomenon in which obesity-induced modifications in gene activity provoke irreversible perturbations in SCD1 gene regulation."

"While these findings may be somewhat discouraging news for those wishing to reverse obesity through dietary interventions, they also highlight the importance of exercise," Muoio said.

Exercise is known to produce robust changes in muscle metabolism, she explained. Further study will examine whether increased physical activity can reverse the elevation in SCD1 or circumvent its effects through independent mechanisms, she added.

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The researchers include Matthew W. Hulver and Michael J. Carper of the Louisiana State University System, Baton Rouge, Louisiana; Jason R. Berggren and G. Joseph A. Houmard of East Carolina University, Greenville, North Carolina; Makoto Miyazaki and James M. Ntambi of the University of Wisconsin, Madison; Eric P. Hoffman of the Children's National Medical Center, Washington, DC; John P. Thyfault and Lynis Dohm of East Carolina University, Greenville, North Carolina; Robert Stevens and Deborah M. Muoio6 of the Duke University Medical Center, Durham, North Carolina. This work was supported by the National Institute of Health Diabetes and Digestive and Kidney Diseases; the Pennington Biomedical Research Foundation and the American Diabetes Association.

Hulver et al.: "Elevated Stearoyl-CoA Desaturase-1 Expression in Skeletal Muscle Contributes to Abnormal Fatty Acid Partitioning in Obese Humans," Publishing in Cell Metabolism Volume 2, October 2005, pages 251-261. DOI 10.1016/j.cmet.2005.09.002 www.cellmetabolism.org

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