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Deficiency of Acyl Coenzyme A:Diacylglycerol Acyltransferase 1 Increases Leptin Sensitivity in Murine Obesity Models

Gladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, and Department of Medicine, University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Robert V. Farese, Jr., M.D., Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, San Francisco, California 94141-9100. E-mail: . bfarese{at}gladstone.ucsf.edu

Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two known enzymes that catalyze the final step in mammalian triglyceride synthesis. We have reported that DGAT1-deficient mice have increased insulin and leptin sensitivity, likely accounting for their protection against diet-induced obesity and insulin resistance. Here we show that DGAT1 deficiency enhanced the response to peripheral leptin infusion in Agouti yellow and leptin-deficient (ob/ob) mice, two genetic models of obesity and insulin resistance. Interestingly, DGAT1 deficiency did not enhance the response to intracerebroventricular leptin infusion. Moreover, DGAT1 deficiency did not alter the expression of key hypothalamic genes involved in leptin signaling or in the regulation of food intake and energy expenditure. Thus, the leptin-sensitizing effect of DGAT1 deficiency is present in both leptin-resistant and leptin-deficient genetic models of obesity and may occur in part by enhancing the effects of leptin in peripheral tissues.

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