Sci. Aging Knowl. Environ., 19 October 2005
Gone to Flab
Overactive lipid-generating enzyme might spur muscles to pack in fat
The muscles of a gym rat and a couch potato don't just look different, they work differently too. The muscles of obese people hoard fat, and a new study might explain why. The work identifies a key lipid-metabolism enzyme that cranks up in hefty individuals and spurs muscle cells to get chubby. Quelling the enzyme might help fend off obesity and diabetes.
Our muscles have two options when it comes to fat: store or burn. The muscles of obese people favor the former, stowing lipids such as triglycerides. Several studies indicate that this buildup prompts insulin resistance, a condition that portends diabetes in which cells stop responding to the hormone. However, researchers don't understand why lipid metabolism goes awry as people become heavy. Animal studies point to one possible trigger, a protein called SCD1 that promotes the production of triglycerides. For example, mice lacking SCD1 remain trim even though they eat more than normal, and their livers amass less triglyceride than do those of unaltered mice. But fat buildup in the muscle as well as in the liver can addle metabolism. Biochemist Matthew Hulver of the Pennington Biomedical Research Center in Baton Rouge, Louisiana, and colleagues wanted to determine whether SCD1 prompts human muscles to lay down lipids.
The researchers first used microarrays to measure gene activity in muscle samples from obese and lean patients. Most genes involved in lipid metabolism were equally active in the two groups. But SCD1 worked harder in the heavyweight individuals. When the researchers cultivated muscle cells from both types of patients, they again found SCD1 hyperactivity in cells of obese patients. Moreover, these cells burned less fat and manufactured almost twice the amount of triglycerides. Obesity itself might ratchet up SCD1 output, Hulver says. But the change persists in cells reared in culture for a month, suggesting that it is genetic or that it results from early-life events, such as malnutrition in the womb, that reprogram metabolism (see "From Womb the Bell Tolls").
To confirm that SCD1 tampers with lipid metabolism, the team engineered muscle cells from lean people to manufacture an excess of the protein. Compared with control cells, the altered muscle cells burned 45% less lipid and stored about 22% more triglycerides. "We've highlighted an enzyme that is contributing to abnormal [lipid] metabolism in human muscle," says Hulver. Researchers now need to determine what fires up SCD1 in obese patients and clarify the molecular pathway that connects SCD1 to fat storage, he says.
Previous work indicated that SCD1 helps control fat accumulation in the liver, but this paper is an impressive demonstration that the protein performs the same job in muscles, says endocrinologist Jeffrey Flier of Harvard Medical School in Boston. The cell culture experiments establish that boosting SCD1 output alters muscle lipid metabolism, adding weight to the conclusion that SCD1 plays a role in obesity-related diseases such as type II diabetes, says exercise physiologist Jeffrey Horowitz of the University of Michigan, Ann Arbor. Future work should determine whether increased SCD1 activity helps drive weight gain, he says. Drug companies are already developing compounds to stall SCD1, Flier notes, and researchers might soon know whether these molecules can prod muscles to let go of their fat.
October 19, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150