Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance

  1. Daniela M.L. Tsukumo1,
  2. Marco A. Carvalho-Filho1,
  3. José B.C. Carvalheira1,
  4. Patrícia O. Prada1,
  5. Sandro M. Hirabara2,
  6. André A. Schenka3,
  7. Eliana P. Araújo1,
  8. José Vassallo3,
  9. Rui Curi2,
  10. Lício A. Velloso1 and
  11. Mario J.A. Saad1
  1. 1Department of Internal Medicine, State University of Campinas, Campinas, São Paulo, Brazil
  2. 2Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
  3. 3Department of Pathology, State University of Campinas, Campinas, São Paulo, Brazil
  1. Address correspondence and reprint requests to Mario J.A. Saad, MD, Departamento de Clínica Médica, FCM-UNICAMP, Cidade Universitária Zeferino Vaz, Campinas, SP, Brazil, 13081-970. E-mail: msaad{at}fcm.unicamp.br


Obesity is associated with insulin resistance and a state of abnormal inflammatory response. The Toll-like receptor (TLR)4 has an important role in inflammation and immunity, and its expression has been reported in most tissues of the body, including the insulin-sensitive ones. Because it is activated by lipopolysaccharide and saturated fatty acids, which are inducers of insulin resistance, TLR4 may be a candidate for participation in the cross-talk between inflammatory and metabolic signals. Here, we show that C3H/HeJ mice, which have a loss-of-function mutation in TLR4, are protected against the development of diet-induced obesity. In addition, these mice demonstrate decreased adiposity, increased oxygen consumption, a decreased respiratory exchange ratio, improved insulin sensitivity, and enhanced insulin-signaling capacity in adipose tissue, muscle, and liver compared with control mice during high-fat feeding. Moreover, in these tissues, control mice fed a high-fat diet show an increase in IκB kinase complex and c-Jun NH2-terminal kinase activity, which is prevented in C3H/HeJ mice. In isolated muscles from C3H/HeJ mice, protection from saturated fatty acid–induced insulin resistance is observed. Thus, TLR4 appears to be an important mediator of obesity and insulin resistance and a potential target for the therapy of these highly prevalent medical conditions.


  • Published ahead of print at http://diabetes.diabetesjournals.org on 22 May 2007. DOI: 10.2337/db06-1595.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted May 18, 2007.
    • Received November 14, 2006.
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  1. Diabetes vol. 56 no. 8 1986-1998
  1. Expression of Concern
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