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Protection from obesity-induced insulin resistance in mice lacking TNF-α function

Abstract

Obesity is highly associated with insulin resistance and is the biggest risk factor for non-insulin-dependent diabetes mellitus1,2,3. The molecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-α is a candidate mediator of insulin resistance in obesity, as it is overexpressed in the adipose tissues of rodents and humans4,5,6,7,8,9,10 and it blocks the action of insulin in cultured cells and whole animals10,11,12,13,14. To investigate the role of TNF-α in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-α and those encoding the two receptors for TNF-α. The absence of TNF-α resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNFα-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues. These results indicate that TNF-α is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.

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Figure 1: Growth curves and adiposity of TNF-α−/−and TNF-α+/+mice.
Figure 2: Measures of glucose homeostasis in TNF-α−/−and TNF-α+/+mice.
Figure 3: Measures of glucose homeostasis in ob/ob and ob/ob p55−/−p75−/−mice.
Figure 4: Circulating free fatty-acid levels in TNF-α−/−and TNF-α+/+mice.
Figure 5: The levels of Glut4 protein in TNF-α−/−and TNF-α+/+mice.
Figure 6: Levels of insulin-stimulated tyrosine phosphorylation of insulin receptor in fat, muscle and liver tissues of TNF-α−/−and TNF-α+/+mice.

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Acknowledgements

We thank J. Perschon for generation of the TNF receptor-deficient mice, and members of the Hotamisligil laboratory for discussions and support. This work is in part supported by grants from the NIH and American Diabetes Foundation (G.S.H.).

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Correspondence to Gkhan S. Hotamisligil.

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Uysal, K., Wiesbrock, S., Marino, M. et al. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997). https://doi.org/10.1038/39335

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