Tumor Necrosis Factor α: A Key Component of the Obesity-Diabetes Link

  1. Bruce M Spiegelman
  1. Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School Boston, Massachusetts
  1. Address correspondence and reprint requests to Dr. Bruce M. Spiegelman, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115.

Abstract

Recent data have suggested a key role for tumor necrosis factor (TNF)-α in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus (NIDDM). TNF-α expression is elevated in the adipose tissue of multiple experimental models of obesity. Neutralization of TNF-α in one of these models improves insulin sensitivity by increasing the activity of the insulin receptor tyrosine kinase, specifically in muscle and fat tissues. On a cellular level, TNF-α is a potent inhibitor of the insulin-stimulated tyrosine phosphorylations on the β-chain of the insulin receptor and insulin receptor substrate-1, suggesting a defect at or near the tyrosine kinase activity of the insulin receptor. Given the clear link between obesity, insulin resistance, and diabetes, these results strongly suggest that TNF-α may play a crucial role in the systemic insulin resistance of NIDDM. This may allow for new treatments of disorders involving resistance to insulin.

  • Received June 17, 1994.
  • Revision received August 19, 1994.
  • Accepted August 19, 1994.
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