DURHAM, N.C. -- The gene encoding an enzyme that hinders muscle fromburning fat manufactures three times more enzyme in the muscle of obesepeople than lean people, researchers from Duke University MedicalCenter and Louisiana State University have found. This causes the obesemuscle tissue to both store more fat and burn less fat, the researcherssaid.
"Obesity is a very complex disease, and this metabolic pathway does notfully explain obesity, but it is a likely contributor," said DeborahMuoio, Ph.D., senior study author and assistant professor of medicineat Duke's Sarah W. Stedman Nutrition and Metabolism Center.
Excess fat storage in muscle tissue is a hallmark of obesity, and maycontribute to problems such as diabetes and cardiovascular disease. Theresearchers discovered that skeletal muscle tissue and cells from obesepeople were programmed to store fat even when removed from the body andforced to grow in the laboratory. This finding suggests the gene ismore active in obese people not only because of excess calorie intake,but also as a result of heritable changes in its regulation, Muoio said.
"The cells of obese people remembered their metabolic program, whichcould help explain, in part, why losing weight and maintaining weightloss is so difficult," Muoio said. "The good news is it's possible tochange your energy balance through exercise. Exercise can enhancemuscle's ability to burn fat," Muoio said. "This discovery alsoprovides a potential drug target."
The results appear in the Oct. 12, 2005 issue of Cell Metabolism. Thework was supported by National Institute of Diabetes & Digestive& Kidney Diseases, of the National Institutes of Health, thePennington Biomedical Research Foundation and the American DiabetesAssociation.
Muoio suspects that the gene's behavior is altered in obese peoplebecause of epigenetic control -- alteration of gene activity stateswithout variations in the DNA code. These changes can be triggered byenvironmental factors, such as nutrition or chemical exposure, andcarried forward even after the stimulus is removed. The geneinvestigated in the study is present in obese and lean people, but wasoverexpressed, or more active, in obese muscle tissue and cells, whichmeans the obese tissue produced larger quantities of enzyme.
In their study, the researchers analyzed stomach muscle tissuedonated by non-diabetic obese and lean people who were having surgery.They examined muscle tissue and muscle satellite cells, which have thepotential to develop into muscle. Both the tissue and cells from obesepeople were programmed to store excess fat in the form of fat droplets.The cells and tissue also burned less fat because they produced more ofan enzyme that opposes fat oxidation. This excess fat storage may belinked to type 2 diabetes because skeletal muscle -- muscle attached tobone -- helps regulate sugar metabolism.
When the muscle satellite cells were encouraged to develop into maturemuscle cells, they showed the same fat storage programming as muscletissue. "This is a very important clue, because it indicates thisprogram of fat storage is perpetuated as these cells divide. It's notdriven strictly by over-nutrition," Muoio said.
To identify the gene controlling this fat storage pathway, the researchteam relied on DNA microarrays, or "gene chips," to test the activityof thousands of genes at once. They also selected a few candidate genes(they chose culprits based on earlier research) to examine by adifferent method. In both cases, they arrived at the same gene, calledsteroyl-CoA desaturase 1 (SCD1), which was known to slow down fatburning and promotes fat storage.
"We found that obesity was associated with a threefold increase in SCD1expression in obese muscle, as well as a threefold higher level of SCD1enzyme, compared to lean muscle," Muoio said. The activity of othergenes linked to fat metabolism and obesity were comparable between thetwo groups.
The researchers also investigated how muscle cells from leanindividuals behaved when forced to overproduce the SCD1 enzyme. Usinggenetic engineering techniques, the team showed that cells from leanpeople mimicked the metabolism of obese cells, storing more fatdroplets and burning less fat, when the amount of SCD1 was increased.
Contributors include Matthew Hulver and Michael Carper, PenningtonBiomedical Research Center, Louisiana State University; Jason Berggren,John Thyfault, G. Lynis Dohm and Joseph Houmard, East CarolinaUniversity; Makoto Miyazaki and James Ntambi, University of Wisconsin,Madison; and Eric Hoffman, Children's National Medical Center.
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