Letters to Nature

Nature 389, 610-614 (9 October 1997) | doi:10.1038/39335; Received 3 June 1997; Accepted 15 August 1997

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

K. Teoman Uysal1,2, Sarah M. Wiesbrock1,2, Michael W. Marino3 and Gkhan S. Hotamisligil1

  1. Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA
  2. Ludwig Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
  3. These authors contributed equally to this study.

Correspondence to: Gkhan S. Hotamisligil1 Correspondence and requests for materials should be addressed to G.S.H. (e-mail: Email: ghotamis@hsph.harvard.edu).

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)-alpha 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-alpha in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of TNF-alpha resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNFalpha-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-alpha is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.