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

Abstract

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.

Suppressive Effects of Insulin on Tumor Necrosis Factor–Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus

“…As previously reported 34, 35, TNF‐knockout mice were partially resistant to the weight gain associated with the HF diet (Figure 5A). Similarly, the TNF‐knockout mice on the HF diet displayed less glucose intolerance than did the wild‐type mice on the HF diet (Figures 5B and C).…”

“…In fact, the TNF‐knockout mouse is known to be resistant to HF diet–induced insulin resistance and obesity 34, 35, a systemic phenotype that was further confirmed herein (Figure 5). Similar conclusions were drawn from investigations using TNF receptor type I–knockout mice 38 and antibody blockade of TNF in mouse models 39, 40, as well as in a few clinical studies 41, 42, 43.…”

Lipid signalling in disease

“…TNF is a pro-inflammatory cytokine that activates various signal transduction cascades, including many of the pathways that are discussed below as crucial inhibitors of insulin action. In obese mouse models with a targeted mutation in the gene encoding TNF insulin sensitivity and glucose homeostasis improved, which confirms that this inflammatory response has a vital role in the regulation of insulin action 71,72 . TNF is also overexpressed in the adipose and muscle tissue of obese humans, and when exogenously administered, causes insulin resistance 73 .…”

Elevated serum tumour necrosis factor-alpha levels can contribute to the insulin resistance in Type II (non-insulin-dependent) diabetes and in obesity

“…In TNF-a deficient obese mice the GLUT-4 protein level was significantly higher only in the muscle tissue [5]. Targeted mutations in the genes of TNF-a and the two TNF-receptors resulted in an improved insulin sensitivity in animal models of obesity [5,6]. According to these observations the role of TNF-a can be raised in insulin resistance and hyperinsulinaemia.…”