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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Immunity and Disease Prevention Research » Research » Publications at this Location » Publication #335826
Title: Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity

Author
item ONO-MOORE, KIKUMI - University Of California
item ZHAO, LING - University Of Tennessee
item Huang, Shurong
item KIM, JEONG-A - University Of Alabama
item RUTKOWSKY, JENNIFER - University Of California
item SNODGRASS, RYAN - University Of California
item Schneider, Dina
item QUON, MICHAEL - University Of Maryland
item GRAHAM, JAMES - University Of California
item HAVEL, PETER - University Of California
item Hwang, Daniel

Submitted to: European Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/20/2017
Publication Date: 8/4/2017
Citation: Ono-Moore, K.D., Zhao, L., Huang, S., Kim, J., Rutkowsky, J.M., Snodgrass, R.G., Schneider, D.A., Quon, M.J., Graham, J.L., Havel, P.J., Hwang, D.H. 2017. Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity. European Journal of Immunology. doi: 10.1002/iid3.162.

Interpretive Summary: Chronic inflammation is associated with obesity and diabetes. However, what causes and mediates this inflammation in these metabolic disorders is not well understood. Pro-inflammatory immune cell receptor TLR4 mediates both infection-induced and non-infection inflammation. 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. Thus, we generated two mouse lines producing increased amounts of TLR4 in adipose tissue and determined whether these mice would show increased insulin resistance. Mice with increased TLR4 production fed a high fat or a normal diet did not exhibit increased insulin resistance compared to control mice despite increased localized inflammation in white adipose tissue. Furthermore, females of one TLR4 mouse line fed a normal chow diet had improved insulin sensitivity compared to control mice. Together, these results suggest that increased 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.

Technical Abstract: Chronic low-grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Tolllike 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. Thus, we 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. 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. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and bodyweight gain when compared with wild type littermates. Together, 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.