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IKK-β links inflammation to obesity-induced insulin resistance


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.


  1. 1

    Kahn, B. B. Type 2 diabetes: when insulin secretion fails to compensate for insulin resistance. Cell 92, 593–596 (1998).

    CAS  Article  Google Scholar 

  2. 2

    Zimmet, P., Alberti, K. G. & Shaw, J. Global and societal implications of the diabetes epidemic. Nature 414, 782–787 (2001).

    CAS  Article  Google Scholar 

  3. 3

    Kahn, B. B. & Flier, J. S. Obesity and insulin resistance. J Clin Invest 106, 473–81 (2000).

    CAS  Article  Google Scholar 

  4. 4

    Klover, P. J., Zimmers, T. A., Koniaris, L. G. & Mooney, R. A. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52, 2784–2789 (2003).

    CAS  Article  Google Scholar 

  5. 5

    Grimble, R. F. Inflammatory status and insulin resistance. Curr. Opin. Clin. Nutr. Metab. Care 5, 551–559 (2002).

    CAS  Article  Google Scholar 

  6. 6

    Pickup, J. C. & Crook, M. A. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 41, 1241–1248 (1998).

    CAS  Article  Google Scholar 

  7. 7

    Pickup, J. C., Mattock, M. B., Chusney, G. D. & Burt, D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 40, 1286–1292 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Festa, A., D'Agostino, R., Jr., Tracy, R. P. & Haffner, S. M. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 51, 1131–1137 (2002).

    CAS  Article  Google Scholar 

  9. 9

    Hotamisligil, G. S. Inflammatory pathways and insulin action. Int. J. Obes. Relat. Metab. Disord. 27 Suppl 3, S53–S55 (2003).

    CAS  Article  Google Scholar 

  10. 10

    Barnes, P. J. & Karin, M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).

    CAS  Article  Google Scholar 

  11. 11

    Chen, L. W. et al. The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat. Med. 9, 575–581 (2003).

    CAS  Article  Google Scholar 

  12. 12

    Kim, J. K. et al. Prevention of fat-induced insulin resistance by salicylate. J. Clin. Invest. 108, 437–446 (2001).

    CAS  Article  Google Scholar 

  13. 13

    Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293, 1673–1677 (2001).

    CAS  Article  Google Scholar 

  14. 14

    Arena, F. P., Dugowson, C. & Saudek, C. D. Salicylate-induced hypoglycemia and ketoacidosis in a nondiabetic adult. Arch. Intern. Med. 138, 1153–1154 (1978).

    CAS  Article  Google Scholar 

  15. 15

    Karin, M., Yamamoto, Y. & Wang, Q. M. The IKK NF-kappa B system: a treasure trove for drug development. Nat. Rev. Drug Discov. 3, 17–26 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Li, Z. W. et al. The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J. Exp. Med. 189, 1839–1845 (1999).

    CAS  Article  Google Scholar 

  17. 17

    Rohl, M. et al. Conditional disruption of IkappaB kinase 2 fails to prevent obesity-induced insulin resistance. J. Clin. Invest. 113, 474–481 (2004).

    Article  Google Scholar 

  18. 18

    Maeda, S. et al. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity 19, 725–737 (2003).

    CAS  Article  Google Scholar 

  19. 19

    Greten, F. R. et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).

    CAS  Article  Google Scholar 

  20. 20

    Lovejoy, J. C. The influence of dietary fat on insulin resistance. Curr. Diab. Rep. 2, 435–440 (2002).

    Article  Google Scholar 

  21. 21

    Hevener, A. L. et al. Muscle-specific Pparg deletion causes insulin resistance. Nat. Med. 9, 1491–1497 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    CAS  Article  Google Scholar 

  23. 23

    Koistinen, H. A. & Zierath, J. R. Regulation of glucose transport in human skeletal muscle. Ann. Med. 34, 410–418 (2002).

    CAS  Article  Google Scholar 

  24. 24

    Whiteman, E. L., Cho, H. & Birnbaum, M. J. Role of Akt/protein kinase B in metabolism. Trends Endocrinol. Metab. 13, 444–451 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Li, Q., Van Antwerp, D., Mercurio, F., Lee, K. F. & Verma, I. M. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 284, 321–325 (1999).

    CAS  Article  Google Scholar 

  26. 26

    Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002).

    CAS  Article  Google Scholar 

  27. 27

    Maeda, S. et al. IKKβ is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFα. Immunity 19, 725–737 (2003).

    CAS  Article  Google Scholar 

  28. 28

    Virkamaki, A. & Yki-Jarvinen, H. Mechanisms of insulin resistance during acute endotoxemia. Endocrinology 134, 2072–2078 (1994).

    CAS  Article  Google Scholar 

  29. 29

    Sugita, H. et al. Inducible nitric oxide synthase plays a role in LPS-induced hyperglycemia and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 282, E386–E394 (2002).

    CAS  Article  Google Scholar 

  30. 30

    Cai, D. et al. Local and systemic insulin resistance due to hepatic activation of IKK-β and NF-kB. Nat. Med. 11, 183–190 (2005).

    CAS  Article  Google Scholar 

  31. 31

    Cai, D. et al. IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119, 285–298 (2004).

    CAS  Article  Google Scholar 

  32. 32

    Samuel, V. T. et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J. Biol. Chem. 279, 32345–32353 (2004).

    CAS  Article  Google Scholar 

  33. 33

    Petersen, K. F., Dufour, S., Befroy, D., Garcia, R. & Shulman, G. I. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350, 664–671 (2004).

    CAS  Article  Google Scholar 

  34. 34

    Moore, K. J. et al. The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nat. Med. 7, 41–47 (2001).

    CAS  Article  Google Scholar 

  35. 35

    Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    CAS  Article  Google Scholar 

  36. 36

    Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Miyazaki, Y., Pipek, R., Mandarino, L. J. & DeFronzo, R. A. Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients. Int. J. Obes. Relat. Metab. Disord. 27, 88–94 (2003).

    CAS  Article  Google Scholar 

  38. 38

    Bruun, J. M., Pedersen, S. B., Kristensen, K. & Richelsen, B. Effects of pro-inflammatory cytokines and chemokines on leptin production in human adipose tissue in vitro. Mol. Cell. Endocrinol. 190, 91–99 (2002).

    CAS  Article  Google Scholar 

  39. 39

    Patti, M. E. Gene expression in humans with diabetes and prediabetes: what have we learned about diabetes pathophysiology? Curr. Opin. Clin. Nutr. Metab. Care 7, 383–390 (2004).

    CAS  Article  Google Scholar 

  40. 40

    Li, Q. & Verma, I. M. NF-κB regulation in the immune system. Nat. Rev. Immunol. 2, 725–734 (2002).

    CAS  Article  Google Scholar 

  41. 41

    Leffert, H. L., Koch, K. S., Moran, T. & Williams, M. Liver cells. Methods Enzymol. 58, 536–544 (1979).

    CAS  Article  Google Scholar 

  42. 42

    Arkan, M. C., Leonarduzzi, G., Biasi, F., Basaga, H. & Poli, G. Physiological amounts of ascorbate potentiate phorbol ester-induced nuclear-binding of AP-1 transcription factor in cells of macrophagic lineage. Free Radic. Biol. Med. 31, 374–382 (2001).

    CAS  Article  Google Scholar 

  43. 43

    Hu, Y. et al. IKKα controls formation of the epidermis independently of NF-κB via a differentiation inducing factor. Nature 410, 710–714 (2001).

    CAS  Article  Google Scholar 

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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).

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