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

Nature Geneticsvolume 25pages8790 (2000) | Download Citation

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Abstract

Triglycerides (or triacylglycerols) represent the major form of stored energy in eukaryotes. Triglyceride synthesis has been assumed to occur primarily through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme that catalyses the final and only committed step in the glycerol phosphate pathway1,2,3. Therefore, Dgat has been considered necessary for adipose tissue 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 resistance 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 synthesis may be useful for treating obesity.

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Acknowledgements

We thank H. Myers for assistance with embryonic stem cell culture; T. Yu for blastocyst injections; S. Erickson for advice concerning Dgat assays; D. Newland for assistance with histology; T. Marcell for assistance with insulin measurements; J. McGuire for assistance with gas chromatography; S. Ammon for assistance with calorimetry measurements; G. Su for assistance with activity measurements; J. Carroll and S. Gonzales for graphics; S. Ordway and G. Howard for editorial assistance; B. Taylor for manuscript preparation; and B. Conklin, R. Farese Sr, J. Herz and K. Weisgraber for helpful comments on the manuscript. This work was supported by the National Institutes of Health, the Sandler Family Supporting Foundation, a Howard Hughes Medical Institute grant for transgenic mice and The J. David Gladstone Institutes.

Author information

Affiliations

  1. Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California, USA

    • Steven J. Smith
    • , Sylvaine Cases
    • , Hubert C. Chen
    • , Eric Sande
    • , Bryan Tow
    • , David A. Sanan
    •  & Robert V. Farese Jr
  2. Gladstone Institute of Neurological Disease, University of California, San Francisco, California, USA

    • Jacob Raber
  3. Cardiovascular Research Institute, University of California , San Francisco, California, USA

    • Steven J. Smith
    • , Sylvaine Cases
    • , Hubert C. Chen
    •  & Robert V. Farese Jr
  4. Department of Medicine, University of California, San Francisco, California, USA

    • Hubert C. Chen
    •  & Robert V. Farese Jr
  5. Department of Neurology, University of California, San Francisco, California, USA

    • Jacob Raber
  6. Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA

    • Dalan R. Jensen
    •  & Robert H. Eckel

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Correspondence to Robert V. Farese Jr.

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https://doi.org/10.1038/75651

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