Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha

Cytokine Growth Factor Rev. 2003 Oct;14(5):447-55. doi: 10.1016/s1359-6101(03)00052-2.


Insulin resistance is a fundamental defect that precedes the development of the full insulin resistance syndrome as well as beta cell failure and type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha), a paracrine/autocrine factor highly expressed in adipose tissues of obese animals and human subjects, is implicated in the induction of insulin resistance seen in obesity and type 2 diabetes. Here, we review several molecular aspects of adipose tissue physiology, and highlight the direct effects of TNF-alpha on the functions of adipose tissue including induction of lipolysis, inhibition of insulin signaling, and alterations in expression of adipocyte important genes through activation of NF-kappaB, as well as their pertinence to insulin sensitivity of adipocytes. We also review the ability of TNF-alpha to inhibit synthesis of several adipocyte-specific proteins including Acrp30 (adiponectin) and enhance release of free fatty acids (FFAs) from adipose tissue, and discuss how these factors may act as systemic mediators of TNF-alpha and affect whole body energy homeostasis and overall insulin sensitivity. On the basis of these mechanisms, we examine the therapeutic potential of blocking specific autocrine/paracrine signaling pathways in adipocytes, particularly those involving NF-kappaB, in the treatment of type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adiponectin
  • Adipose Tissue / physiology*
  • Animals
  • Diabetes Mellitus, Type 2 / metabolism
  • Energy Metabolism / physiology
  • Fatty Acids, Nonesterified / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / physiology*
  • Intercellular Signaling Peptides and Proteins*
  • Proteins / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*


  • Adiponectin
  • Fatty Acids, Nonesterified
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Proteins
  • Tumor Necrosis Factor-alpha