Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice.
To address the hypothesis that tumor necrosis factor (TNF)-alpha has a role in obesity-associated insulin resistance or the regulation of in vivo lipid metabolism, mice with targeted disruption of the TNF-alpha gene were generated and studied. The absence of TNF-alpha 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-treatment 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-alpha functions to regulate plasma triglycerides and body adiposity and 2) that although TNF-alpha contributes to reduced insulin sensitivity in older or obese mice, the absence of TNF-alpha is not sufficient to substantially protect against insulin resistance in the GTG hyperphagic model of rodent obesity.
Ventre
J
J
Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Doebber
T
T
Wu
M
M
MacNaul
K
K
Stevens
K
K
Pasparakis
M
M
Kollias
G
G
Moller
D E
DE
D000818:Animals; D006051:Aurothioglucose / Q000494:pharmacology; D007031:Hypothalamus / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D007328:Insulin; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D006051:Aurothioglucose