IKK-β links inflammation to obesity-induced insulin resistance

Abstract

Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IκB kinase β (IKK-β, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-κB. To understand the role of IKK-β in insulin resistance, we used mice lacking this enzyme in hepatocytes (IkbkbΔhep) or myeloid cells (IkbkbΔmye). IkbkbΔhep mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, IkbkbΔmye mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK-β acts locally in liver and systemically in myeloid cells, where NF-κB activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK-β in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-β, especially in myeloid cells, may be used to treat insulin resistance.

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Figure 1: Liver-specific Ikbkb deletion improves hepatic insulin sensitivity.
Figure 2: Liver-specific Ikbkb deletion enhances insulin signaling.
Figure 3: Inhibition of NF-κB prevents inflammation-induced insulin resistance.
Figure 4: Deletion of IKK-β in myeloid cells improves systemic insulin sensitivity.
Figure 5: IkbkbΔhep and IkbkbΔmye mice remain glucose tolerant during inflammation-induced insulin resistance.

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Acknowledgements

Research was supported by grants from the US National Institutes of Health to M.K. (ES06376), J.O. (DK33651), and A.H. (DK60484) and Italian Ministry of University to G.P. (FIRB2001, RBAU01JBH8). M.K. is an American Cancer Society Research Professor. M.C.A. was funded by a Mentor-Based Postdoctoral Fellowship from the American Diabetes Association to M.K.

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Correspondence to Jerrold Olefsky or Michael Karin.

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Arkan, M., Hevener, A., Greten, F. et al. IKK-β links inflammation to obesity-induced insulin resistance. Nat Med 11, 191–198 (2005). https://doi.org/10.1038/nm1185

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