Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance
Abstract
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.
- CLS, crown-like structure
- ELISA, enzyme-linked immunosorbent assay
- FFA, free fatty acid
- HFD, high-fat diet
- IGTT, intraperitoneal glucose tolerance test
- IκBα, inhibitor of nuclear factor-κB
- IKKβ, IκB kinase complex
- IL, interleukin
- IR, insulin receptor
- IRS-1, insulin receptor substrate-1
- JNK, c-Jun NH2-terminal kinase
- LPS, lipopolysaccharide
- NK-κB, nuclear factor-κB
- RER, respiratory exchange ratio
- TNF, tumor necrosis factor
- TLR, Toll-like receptor
- WAT, white adipose tissue
- Received November 14, 2006.
- Accepted May 18, 2007.
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