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

Abstract

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.

References

  1. Neel, J.V. Diabetes mellitus: a 'thrifty' genotype rendered detrimental by 'progress'? Am. J. Hum. Genet. 14, 353–362 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Muoio, D.M. & Newgard, C.B. Obesity-related derangements in metabolic regulation. Annu. Rev. Biochem. 75, 367–401 (2006).

    CAS  Article  Google Scholar 

  3. The Food and Agricultural Organization of the United Nations. Food Consumption: Dietary Energy, Protein and Fat. http://www.fao.org/ faostat/foodsecurity/index_en.htm (2008).

  4. Bell, R.M. & Coleman, R.A. Enzymes of glycerolipid synthesis in eukaryotes. Annu. Rev. Biochem. 49, 459–487 (1980).

    CAS  Article  Google Scholar 

  5. Senior, J.R. & Isselbacher, K.J. Direct esterification of monoglycerides with palmityl coenzyme A by intestinal epithelial subcellular fractions. J. Biol. Chem. 237, 1454–1459 (1962).

    CAS  PubMed  Google Scholar 

  6. Kayden, H.J., Senior, J.R. & Mattson, F.H. The monoglyceride pathway of fat absorption in man. J. Clin. Invest. 46, 1695–1703 (1967).

    CAS  Article  Google Scholar 

  7. Mattson, F.H. & Volpenhein, R.A. The digestion and absorption of triglycerides. J. Biol. Chem. 239, 2772–2777 (1964).

    CAS  PubMed  Google Scholar 

  8. Yen, C.-L.E., Stone, S.J., Cases, S., Zhou, P. & Farese, R.V., Jr. Identification of a gene encoding MGAT1, a monoacylglylcerol acyltransferase. Proc. Natl. Acad. Sci. USA 99, 8512–8517 (2002).

    CAS  Article  Google Scholar 

  9. Yen, C.-L.E. & Farese, R.V., Jr. MGAT2, a monoacylglycerol acyltransferase expressed in the small intestine. J. Biol. Chem. 278, 18532–18537 (2003).

    CAS  Article  Google Scholar 

  10. Cao, J., Lockwood, J., Burn, P. & Shi, Y. Cloning and functional characterization of a mouse intestinal acyl-CoA:monoacylglycerol acyltransferase, MGAT2. J. Biol. Chem. 278, 13860–13866 (2003).

    CAS  Article  Google Scholar 

  11. Cheng, D. et al. Identification of acyl coenzyme A:monoacylglycerol acyltransferase 3, an intestinal specific enzyme implicated in dietary fat absorption. J. Biol. Chem. 278, 13611–13614 (2003).

    CAS  Article  Google Scholar 

  12. Cao, J. et al. A predominant role of acyl-CoA:monoacylglycerol acyltransferase-2 in dietary fat absorption implicated by tissue distribution, subcellular localization, and up-regulation by high fat diet. J. Biol. Chem. 279, 18878–18886 (2004).

    CAS  Article  Google Scholar 

  13. Jandacek, R.J., Heubi, J.E. & Tso, P. A novel, noninvasive method for the measurement of intestinal fat absorption. Gastroenterology 127, 139–144 (2004).

    CAS  Article  Google Scholar 

  14. Yen, C.-L.E., Monetti, M., Burri, B.J. & Farese, R.V., Jr. The triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters. J. Lipid Res. 46, 1502–1511 (2005).

    CAS  Article  Google Scholar 

  15. Baggio, L.L. & Drucker, D.J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131–2157 (2007).

    CAS  Article  Google Scholar 

  16. Lowell, B.B. & Spiegelman, B.M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000).

    CAS  Article  Google Scholar 

  17. Krauss, S., Zhang, C.Y. & Lowell, B.B. The mitochondrial uncoupling-protein homologues. Nat. Rev. Mol. Cell Biol. 6, 248–261 (2005).

    CAS  Article  Google Scholar 

  18. Scrocchi, L.A. et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat. Med. 2, 1254–1258 (1996).

    CAS  Article  Google Scholar 

  19. Bouchard, C., Pérusse, L., Chagnon, Y., Warden, C. & Ricquier, D. Linkage between markers in the vicinity of the uncoupling protein 2 gene and resting metabolic rate in humans. Hum. Mol. Genet. 6, 1887–1889 (1997).

    CAS  Article  Google Scholar 

  20. Snyder, F. & Stephens, N. A simplified spectrophotometric determination of ester groups in lipids. Biochim. Biophys. Acta 34, 244–245 (1959).

    CAS  Article  Google Scholar 

  21. Hamilton, R.L., Jr., Goerke, J., Guo, L.S.S., Williams, M.C. & Havel, R.J. Unilamellar liposomes made with the French pressure cell: A simple preparative and semiquantitative technique. J. Lipid Res. 21, 981–992 (1980).

    CAS  PubMed  Google Scholar 

  22. Iqbal, J. & Hussain, M. Evidence for multiple complementary pathways for efficient cholesterol absorption in mice. J. Lipid Res. 46, 1491–1501 (2005).

    CAS  Article  Google Scholar 

  23. Cases, S. et al. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J. Biol. Chem. 276, 38870–38876 (2001).

    CAS  Article  Google Scholar 

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Acknowledgements

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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Supplementary Figs. 1–5 and Suppmentary Methods (PDF 14912 kb)

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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). https://doi.org/10.1038/nm.1937

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