PT  - JOURNAL ARTICLE
AU  - Ventre, John
AU  - Doebber, Thomas
AU  - Wu, Margaret
AU  - MacNaul, Karen
AU  - Stevens, Karla
AU  - Pasparakis, Manolis
AU  - Kollias, George
AU  - Moller, David E
TI  - Targeted Disruption of the Tumor Necrosis Factor-α Gene: Metabolic Consequences in Obese and Nonobese Mice
AID  - 10.2337/diab.46.9.1526
DP  - 1997 Sep 01
TA  - Diabetes
PG  - 1526--1531
VI  - 46
IP  - 9
4099  - http://diabetes.diabetesjournals.org/content/46/9/1526.short
4100  - http://diabetes.diabetesjournals.org/content/46/9/1526.full
SO  - Diabetes1997 Sep 01; 46
AB  - 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.