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Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB

Abstract

We show that NF-κB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-κB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1β and TNF-α, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-β. Hepatic expression of the IκBα superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-κB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.

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Figure 1: IKK-β and NF-κB activities in liver.
Figure 2: Carbohydrate metabolism.
Figure 3: Insulin signaling in liver and skeletal muscle of LIKK mice.
Figure 4: Cytokine signaling in LIKK mice.
Figure 5: Reversal of insulin resistance and inflammation.

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Acknowledgements

The authors wish to thank Y. Guo, E. Werner and B. C. Oh for suggestions and technical assistance. D.C. was supported by a Mentor-Based postdoctoral fellowship from the American Diabetes Association. These studies were funded by US National Institutes of Health grants R01 DK45493 and R01 DK51729 (S.E.S.), P30 DK36836 (Joslin Diabetes Center) and the Helen and Morton Adler Chair (S.E.S.).

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Correspondence to Steven E Shoelson.

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Supplementary information

Supplementary Fig. 1

β cell morphometry and function in LIKK mice. (PDF 132 kb)

Supplementary Fig. 2

IL-6 localization in liver. (PDF 60 kb)

Supplementary Fig. 3

β cell morphometry and function is LISR mice. (PDF 118 kb)

Supplementary Fig. 4

Superrepressor concentration and NF-κB activity in LISR mice. (PDF 24 kb)

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Cai, D., Yuan, M., Frantz, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat Med 11, 183–190 (2005). https://doi.org/10.1038/nm1166

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