A gene that programs muscle tissue to store fat is over-expressed in obese women, researchers here say, and may be a key reason why dieting fails.

The gene, dubbed stearoyl-CoA desaturase 1, or SCD1, codes for an enzyme that catalyzes the synthesis of monounsaturated fatty acids. It is up-regulated in skeletal muscle taken from obese women, compared with muscle from lean women, according to Deborah Muoio, Ph.D., of Duke Medical Center.

The increased expression of the gene starts a cascade of cellular events that culminates in increased fat storage in muscle tissue, Dr. Muoio and colleagues concluded in the October issue of Cell Metabolism.

The finding links the lipid metabolism malfunctions seen in obesity and Type 2 diabetes with a genetic underpinning, Dr. Muoio said. “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,” she said.

SCD1 is “at least a very important contributor” to those changes, she added.

“There are two important observations that might have clinical relevance,” Dr. Muoio said. The first is that SCD1 and any other mechanisms that mediate obesity-associated changes in muscle lipid metabolism provide a possible target for drug development, she said in an interview.

The second observation is that muscle cells from obese subjects - even after several generations of growth outside the body - still store more fat than cells from lean subjects, she said.

“That tells us that the program is being perpetuated even in the absence of the obese environment,” Dr. Muoio said, “and the implication there is that it may explain why certain individuals have difficulty losing weight or maintaining weight loss.”

Using DNA micro-array technology, the researchers compared tissue from the rectus abdominis muscle of eight women whose body mass index (BMI) was greater than 35 to similar tissue from eight women with a body mass index of less than 25.

In a previous study, the researchers had shown that the obese individuals were not yet diabetic, but did exhibit severe insulin resistance; their muscle was interlaced with fat droplets and they also had a 43% decrease in their ability to metabolize fat, compared with lean individuals.

In this study, the DNA micro-array technology showed that the muscle tissue of the obese women had roughly three times the levels of SCD1 than the muscle of the lean women. The obese women had 3.48 times (plus or minus 1.25) the SCD1 of the lean women; the difference was statistically significant at the p<0.05 confidence level.

To try to rule out the possibility that the elevated SCD1 is a consequence of obesity, the researchers evaluated primary human skeletal myocytes (HSKMC) from the lean and obese women.

Even after several generations, the researchers found that the HSKMC cultures from the obese women still had abnormal accumulation of fat droplets and reduced fatty acid catabolism.

Also, they had levels of SCD1 that were almost three times higher than those in HSKMC derived from lean women, even though both sets of cultures shared a common nutritional environment.

Finally, the researchers took myotubes from the lean participants and transfected the SCD1 gene; the resulting constructs showed a greater tendency to store fat than to burn it, like the muscle tissue of the obese subjects.

Taken together, the findings suggest that in obese individuals either inherited or imprinted genetic factors may cause irreversible changes in SCD1 production, Dr. Muoio said.

Exactly why such changes might take place remains unclear; Dr. Muoio speculated that the over-expression of SCD1 is an adaptation designed to ensure that the mitochondria - the powerhouses of the cell - are not overwhelmed by too much fat.

For now the take-home message for clinicians treating obese people is that diet alone is unlikely to have much effect, Dr. Muoio said.

Exercise, on the other hand, is known to produce changes in muscle metabolism; she and colleagues are now investigating whether increased activity lowers the expression of SCD1 or circumvents its effects in other ways.

The finding “may be somewhat discouraging news for those wishing to reverse obesity through dietary interventions,” Dr. Muoio said, but “they also highlight the importance of exercise.”