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

¹ Department of Internal Medicine, State University of Campinas, Campinas, São Paulo, Brazil
² Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
³ Department of Pathology, State University of Campinas, Campinas, São Paulo, Brazil

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

Abbreviations: CLS, crown-like structure; ELISA, enzyme-linked immunosorbent assay; FFA, free fatty acid; HFD, high-fat diet; IGTT, intraperitoneal glucose tolerance test; IB, inhibitor of nuclear factor-B; IKKß, IB kinase complex; IL, interleukin; IR, insulin receptor; IRS-1, insulin receptor substrate-1; JNK, c-Jun NH₂-terminal kinase; LPS, lipopolysaccharide; NK-B, nuclear factor-B; RER, respiratory exchange ratio; TNF, tumor necrosis factor; TLR, Toll-like receptor; WAT, white adipose tissue

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 IB 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.

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