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New Gladstone/UCSF study finds inhibiting fat synthesis results in obesity resistance in mice

University of California - San Francisco

The regulation of fat mass in the body appears to be more complicated than previously thought, according to new study findings. Researchers from the Gladstone Institute of Cardiovascular Disease and the University of California, San Francisco report their findings in the May issue of Nature Genetics.

One key step in fat regulation is the production, or synthesis, of triglycerides, the major component of fat and stored energy in mammals. This process is carried out by an enzyme called DGAT, for acyl CoA:diacylglycerol acyltransferase.

It might be expected that when DGAT is not present, triglycerides are not produced, but a Gladstone/UCSF team found this is not the case. In studies with mice, the researchers inactivated the gene that produces DGAT, then compared these animals with their normal cousins. They found that the DGAT-deficient mice produced less triglycerides than normal mice, but were still healthy. (A certain level of fat in body tissues is critical to good health and survival.)

When normal mice were fed a high-fat diet, they became obese. The DGAT-deficient mice, however, were lean and resistant to diet-induced obesity. Moreover, they had a higher metabolic rate and expended more energy, in part because they were more active. DGAT-deficiency also affected metabolism in other tissues, including causing an impairment in milk production in females. "Our findings indicate that multiple mechanisms exist for triglyceride synthesis, rather than a single mechanism as previously thought. They also suggest that specifically blocking DGAT-mediated triglyceride synthesis may be a potential strategy for treating obesity," said senior study investigator Robert V. Farese, Jr., MD, Gladstone scientist and UCSF Associate Professor of Medicine.

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Steven Smith, PhD, a postdoctoral fellow, was the lead study investigator. He and Farese were part of a Gladstone/UCSF team that two years ago found the gene that encodes DGAT.

In addition to Farese and Smith, co-investigators of the current study are Sylvaine Cases, PhD, Hubert C. Chen, MD, and Jacob Raber, PhD, of Gladstone/UCSF, Eric Sande, Bryan Tow, and David Sanan, PhD, of Gladstone; Dalan R. Jensen, PhD, and Robert H. Eckel, MD, of the University of Colorado.

The research was supported by the National Institutes of Health, the Sandler Family Supporting Foundation, the Howard Hughes Medical Institute, and The J. David Gladstone Institutes.

The Gladstone Institute of Cardiovascular Disease, established in 1979, focuses on the study of cholesterol and lipid metabolism and their impacts on cardiovascular disease. The Institute is one of three that make up The J. David Gladstone Institutes, a private biomedical research institute affiliated with UCSF.

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