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Title: Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

Author
item JIA, LIN - University Of Texas Southwestern Medical Center
item VIANNA, CLAUDIA - University Of Texas Southwestern Medical Center
item FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC)
item BERGLUND, ERIC - University Of Texas Southwestern Medical Center
item LIU, CHEN - University Of Texas Southwestern Medical Center
item TAO, CAROLINE - University Of Texas Southwestern Medical Center
item SUN, KAI - University Of Texas Southwestern Medical Center
item LIU, TIEMIN - University Of Texas Southwestern Medical Center
item HARPER, MATTHEW - University Of Texas Southwestern Medical Center
item LEE, CHARLOTTE - University Of Texas Southwestern Medical Center
item LEE, SYANN - University Of Texas Southwestern Medical Center
item SCHERER, PHILIPP - University Of Texas Southwestern Medical Center
item ELMQUIST, JOEL - University Of Texas Southwestern Medical Center

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/11/2014
Publication Date: 5/12/2014
Citation: Jia, L., Vianna, C.R., Fukuda, M., Berglund, E.D., Liu, C., Tao, C., Sun, K., Liu, T., Harper, M.J., Lee, C.E., Lee, S., Scherer, P.E., Elmquist, J.K. 2014. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nature Communications. 5:3878.

Interpretive Summary: Chronic inflammation is a hallmark of obesity and may contribute to the development of obesity-related disorders. Toll-like receptor 4 (Tlr4), a protein found in the body, is a key mediator of inflammatory responses. Although mice lacking Tlr4s in their bodies were previously reported to be protected from diet-induced insulin resistance and inflammation, it was unclear which Tlr4-expressing organs mediated this effect. Here we show that mice deficient in Tlr4 in the liver (Tlr4LKO) exhibited improved glucose balance and alleviated fatty liver disease, even if they became obese after a high-fat diet challenge. Furthermore, Tlr4LKO mice had reduced inflammatory markers. In contrast, the loss of Tlr4 activity in bone marrow cells had little effect on insulin sensitivity. Collectively, these data indicate that the activation of Tlr4 on liver cells contributes to obesity-associated inflammation and insulin resistance. This suggests that targeting Tlr4 on liver cells might be a useful therapeutic strategy for the treatment of type 2 diabetes.

Technical Abstract: Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammation; however, which Tlr4-expressing cells mediate this effect is unknown. Here we show that mice deficient in hepatocyte Tlr4 (Tlr4LKO) exhibit improved glucose tolerance, enhanced insulin sensitivity and ameliorated hepatic steatosis despite the development of obesity after a high-fat diet (HFD) challenge. Furthermore, Tlr4LKO mice have reduced macrophage content in white adipose tissue, as well as decreased tissue and circulating inflammatory markers. In contrast, the loss of Tlr4 activity in myeloid cells has little effect on insulin sensitivity. Collectively, these data indicate that the activation of Tlr4 on hepatocytes contributes to obesity-associated inflammation and insulin resistance, and suggest that targeting hepatocyte Tlr4 might be a useful therapeutic strategy for the treatment of type 2 diabetes.