Those wishing to reverse obesity through dietary interventions may be frustrated in their efforts. However, exercise is known to produce robust changes in muscle metabolism.

But the news is not all bad. Exercise might be more successful than cutting calories in overriding the aberrant metabolic program in muscle, the researchers say, thereby improving the long-term prognosis of those prone to obesity.

Enzyme Implicated

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 researchers found. This elevation in enzyme activity points to an important link between obesity, diabetes and abnormal fat buildup in muscle, says 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 says. "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 and also showed a 43% decline in the ability to burn fat.

The research team developed a comprehensive profile of gene activity, which revealed a link between obesity and a three-fold increase in muscle SCD1 levels. That increase in enzyme expression and activity 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, the researchers report.

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

Importance of Exercise

The muscular abnormalities seen in obese individuals may stem from an inherited genetic predisposition or from imprinted defects in metabolic genes, Muoio suggests. 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," report the researchers.

"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," they note.

"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 points out.

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