Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat

Triglycerides (or triacylglycerols) represent the major form of stored ener gy in eukaryotes. Triglyceride synthesis has been assumed to occur primaril y through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme t hat catalyses the final and only committed step in the glycerol phosphate p athway(1-3). Therefore, Dgat has been considered necessary for adipose tiss ue formation and essential for survival. Here we show that Dgat-deficient ( Dgat(-/-)) mice are viable and can still synthesize triglycerides, Moreover , these mice are lean and resistant to diet-induced obesity. The obesity re sistance involves increased energy expenditure and increased activity. Dgat deficiency also alters triglyceride metabolism in other tissues, including the mammary gland, where lactation is defective in Dgat(-/-) females. Our findings indicate that multiple mechanisms exist for triglyceride synthesis and suggest that the selective inhibition of Dgat-mediated triglyceride sy nthesis may be useful for treating obesity.