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Loss-of-function mutation in TLR4 prevents diet-induced obesity and insulin resistance

¹Department of Internal Medicine, State University of Campinas, 13081-970, Campinas, SP, Brazil;
²Department of Physiology and Byophisics, Institute of Biomedical Sciences, University of São Paulo, SP, Brazil;
³Department of Pathology, State University of Campinas, Campinas, SP, Brazil.

Correspondence: msaad{at}fcm.unicamp.br

Key Words: obesity • insulin resistance • TLR4.

Obesity is associated with insulin resistance and a state of abnormal inflammatory response. The Toll-like receptor 4 (TLR4) 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. Since it is activated by lipopolysaccharide (LPS) 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, as compared to control mice during high fat feeding. Moreover, in these tissues, control mice fed on a high fat diet show an increase in IKKß and JNK activity, which is prevented in C3H/HeJ mice. In isolated muscles from C3H/HeJ a 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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