Abstract
IntroductionChronic low‐grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll‐like receptor 4 (TLR4) mediates both infection‐induced and sterile inflammation by recognizing pathogen‐associated molecular patterns and endogenous molecules, respectively. Saturated fatty acids can activate TLR4, and TLR4‐deficient mice were protected from high fat diet (HFD)‐induced obesity and insulin resistance, suggesting that TLR4‐mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance.MethodsWe generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance.ResultsTG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild‐type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild‐type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet.ConclusionsTogether, these results suggest that constitutively active TLR4‐induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet‐induced insulin resistance may require other signals in addition to TLR4‐mediated inflammation.
Highlights
Chronic low-grade inflammation is associated with obesity and diabetes
Females of one line of TG mice fed a normal chow diet (NCD) exhibited improved insulin sensitivity and decreased adiposity. These results suggest that enhanced Toll-like receptor 4 (TLR4)-mediated inflammation in adipose tissue alone does not lead to impairment of systemic insulin sensitivity in mice, and that TLR4-mediated inflammation may be necessary but not sufficient to induce the development of insulin resistance (IR)
DTLR4 transgene under aP2 promoter is expressed in adipose tissue and bone marrow derived macrophages (BMDM)
Summary
Chronic low-grade inflammation is associated with obesity and diabetes. what causes and mediates chronic inflammation in metabolic disorders is not well understood. Saturated fatty acids can activate TLR4, and TLR4-deficient mice were protected from high fat diet (HFD)induced obesity and insulin resistance, suggesting that TLR4-mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance. Results: TG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild-type controls despite increased localized inflammation in white adipose tissue. Conclusions: Together, these results suggest that constitutively active TLR4induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet-induced insulin resistance may require other signals in addition to TLR4-mediated inflammation. Toll-like receptors (TLRs) can induce innate immune responses by recognizing invariant pathogen-associated molecular patterns, leading to activation of downstream signaling pathways and the expression of diverse arrays of proinflammatory marker gene products that are required for host defense against invading pathogens. Results from genetic, clinical, and biochemical studies suggest that TLR-mediated inflammation is an important determinant in modifying the risk of the development of many chronic diseases, including diabetes and cardiovascular disease [6]
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