on November 29, 2004
Published online before print November 29, 2004, doi: 10.1161/01.ATV.0000151874.81059.ad
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Submitted on August 20, 2004
Accepted on November 15, 2004
Inhibition of Triglyceride Synthesis as a Treatment Strategy for Obesity. Lessons From DGAT1-Deficient Mice
Hubert C. Chen and Robert V. Farese Jr *
From the Department of Medical Sciences (H.C.C.), Amgen Inc, Thousand Oaks, Calif; Gladstone Institute of Cardiovascular Disease (R.V.F.), San Francisco, Calif; and Department of Medicine (R.V.F.), University of California, San Francisco, Calif.
* To whom correspondence should be addressed. E-mail: bfarese{at}gladstone.ucsf.edu.
Abstract--Because the ability to make triglycerides is essential for the accumulation of adipose tissue, inhibition of triglyceride synthesis may ameliorate obesity and its related medical consequences. Acyl coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) is 1 of 2 DGAT enzymes that catalyze the final reaction in the known pathways of mammalian triglyceride synthesis. Mice lacking DGAT1 are resistant to obesity and have increased sensitivity to insulin and leptin. DGAT1-deficient mice are also resistant to diet-induced hepatic steatosis. The effects of DGAT1 deficiency on energy and glucose metabolism result in part from the altered secretion of adipocyte-derived factors. Although complete DGAT1 deficiency causes alopecia and impairs development of the mammary gland, these abnormalities are not observed in mice with partial DGAT1 deficiency. These findings suggest that pharmacological inhibition of DGAT1 may be a feasible therapeutic strategy for human obesity and type 2 diabetes.
Key words: acyl CoA:diacylglycerol acyltransferase • energy • glucose • metabolism • insulin resistance • type 2 diabetes
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