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Rapid Publications

Targeted Disruption of the Tumor Necrosis Factor-α Gene: Metabolic Consequences in Obese and Nonobese Mice

  1. John Ventre,
  2. Thomas Doebber,
  3. Margaret Wu,
  4. Karen MacNaul,
  5. Karla Stevens,
  6. Manolis Pasparakis,
  7. George Kollias and
  8. David E Moller
  1. Departments of Molecular Endocrinology, Merck Research Laboratories Rahway, New Jersey
  2. Laboratory Animal Resources, Merck Research Laboratories Rahway, New Jersey
  3. Hellenic Pasteur Institute Athens, Greece
  1. Address correspondence and reprint requests to Dr. Thomas Doebber, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065.
Diabetes 1997 Sep; 46(9): 1526-1531. https://doi.org/10.2337/diab.46.9.1526
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Abstract

To address the hypothesis that tumor necrosis factor (TNF)-α has a role in obesity-associated insulin resistance or the regulation of in vivo lipid metabolism, mice with targeted disruption of the TNF-α gene were generated and studied. The absence of TNF-α protein in TNF-null (−/−) mice was confirmed. Lean or obese (gold-thioglucose [GTG]-injected) homozygous (−/−) mice were compared with lean or obese age- and sex-matched wild-type (+/+) mice derived from the same line at 13, 19, and 28 weeks of age. The following parameters were significantly affected in lean −/− versus +/+ mice: Body weight was not affected until week 28 (decreased by 14%); epididymal fat pad weight also decreased (25%) at this time, as did percentage body fat (16%), while percentage body protein was increased 13%. Fed plasma insulin levels decreased 47% (28 weeks), triglyceride levels decreased (all three ages; maximum 35% at 19 weeks), and fed plasma leptin decreased 33% (28 weeks). Fasting glucose was slightly (10%) reduced, but the glucose response to an oral glucose tolerance test (OGTT) was not affected. There was a trend (NS) toward increased total adipose tissue lipoprotein lipase in −/− versus +/+ mice. GTG-treat-ment resulted in obese −/− and +/+ mice with equal mean body weights (42 and 58% increased weight versus lean mice). The following parameters were significantly different in obese −/− mice: fasting plasma glucose decreased 13% (28 weeks), fed plasma insulin decreased 67% (28 weeks), and insulin response to OGTT was decreased by 50%. For both groups of obese mice, glucose levels during the OGTT were substantially increased compared with those in lean mice; however, mean stimulated glucose levels were 20% lower in obese −/− versus +/+ mice. We conclude 1) that TNF-α functions to regulate plasma triglycerides and body adiposity and 2) that although TNF-α contributes to reduced insulin sensitivity in older or obese mice, the absence of TNF-α is not sufficient to substantially protect against insulin resistance in the GTG hyperphagic model of rodent obesity.

  • Received March 20, 1997.
  • Revision received June 30, 1997.
  • Accepted June 30, 1997.
  • Copyright © 1997 by the American Diabetes Association
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Targeted Disruption of the Tumor Necrosis Factor-α Gene: Metabolic Consequences in Obese and Nonobese Mice
John Ventre, Thomas Doebber, Margaret Wu, Karen MacNaul, Karla Stevens, Manolis Pasparakis, George Kollias, David E Moller
Diabetes Sep 1997, 46 (9) 1526-1531; DOI: 10.2337/diab.46.9.1526

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Targeted Disruption of the Tumor Necrosis Factor-α Gene: Metabolic Consequences in Obese and Nonobese Mice
John Ventre, Thomas Doebber, Margaret Wu, Karen MacNaul, Karla Stevens, Manolis Pasparakis, George Kollias, David E Moller
Diabetes Sep 1997, 46 (9) 1526-1531; DOI: 10.2337/diab.46.9.1526
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