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Deficiency of the intestinal enzyme acyl CoA:monoacylglycerol acyltransferase-2 protects mice from metabolic disorders induced by high-fat feeding


Animals are remarkably efficient in absorbing dietary fat and assimilating this energy-dense nutrient into the white adipose tissue (WAT) for storage. Although this metabolic efficiency may confer an advantage in times of calorie deprivation, it contributes to obesity and associated metabolic disorders when dietary fat is abundant1,2. Here we show that the intestinal lipid synthesis enzyme acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has a crucial role in the assimilation of dietary fat and the accretion of body fat in mice. Mice lacking MGAT2 have a normal phenotype on a low-fat diet. However, on a high-fat diet, MGAT2-deficient mice are protected against developing obesity, glucose intolerance, hypercholesterolemia and fatty livers. Caloric intake is normal in MGAT2-deficient mice, and dietary fat is absorbed fully. However, entry of dietary fat into the circulation occurs at a reduced rate. This altered kinetics of fat absorption apparently results in more partitioning of dietary fat toward energy dissipation rather than toward storage in the WAT. Thus, our studies identify MGAT2 as a key determinant of energy metabolism in response to dietary fat and suggest that the inhibition of this enzyme may prove to be a useful strategy for treating obesity and other metabolic diseases associated with excessive fat intake.

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Figure 1: MGAT2-deficient mice are protected from obesity induced by high-fat feeding.
Figure 2: MGAT2-deficient mice are protected from metabolic disorders induced by high-fat feeding.
Figure 3: MGAT2-deficient mice show increased energy expenditure and body temperature.
Figure 4: Fat absorption in MGAT2-deficient mice is quantitatively normal but delayed.


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We thank R. Jandacek at the University of Cincinnati Mouse Phenotyping Center for measuring lipid absorption; J.D. Fish for histological assistance; D. Walker for assistance with in situ hybridizations; D. Dubiel and K. Veenstra for measuring PYY and GLP-1; R. Bituin for mouse husbandry; Q. Walker for blastocyst microinjections; S. Ordway and G. Howard for editorial assistance; D. Jones for manuscript preparation; members of the Farese laboratory, M. Hirschey and M. Brown for insightful discussions; and R. Mahley and D. Srivastava for comments on the manuscript. This work was supported by funding from the American Heart Association (Scientist Development Grant to C.-L.E.Y.), the US National Institutes of Health (DK-056084 to R.V.F. Jr.), the US National Center for Research Resources (C06 RR018928), and the J. David Gladstone Institutes.

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C.-L.E.Y. designed and conducted experiments, coordinated the project and co-wrote the manuscript; M.-L.C., J.M., C.G., P.Z. and J.S.W. performed phenotyping experiments; B.H. and S.M. performed hormone assays; R.V.F. Jr directed the project and co-wrote the manuscript.

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Correspondence to Robert V Farese Jr.

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Yen, CL., Cheong, ML., Grueter, C. et al. Deficiency of the intestinal enzyme acyl CoA:monoacylglycerol acyltransferase-2 protects mice from metabolic disorders induced by high-fat feeding. Nat Med 15, 442–446 (2009).

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