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NF-κB–inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action

Nature Medicine volume 18, pages 943–949 (2012)Cite this article

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Abstract

The canonical inhibitor of nuclear factor κB kinase subunit β (IKK-β)–nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB1) pathway has been well documented to promote insulin resistance; however, the noncanonical NF-κB–inducing kinase (NIK)–NF-κB2 pathway is not well understood in obesity. Additionally, the contribution of counter-regulatory hormones, particularly glucagon, to hyperglycemia in obesity is unclear. Here we show that NIK promotes glucagon responses in obesity. Hepatic NIK was abnormally activated in mice with dietary or genetic obesity. Systemic deletion of Map3k14, encoding NIK, resulted in reduced glucagon responses and hepatic glucose production (HGP). Obesity is associated with high glucagon responses, and liver-specific inhibition of NIK led to lower glucagon responses and HGP and protected against hyperglycemia and glucose intolerance in obese mice. Conversely, hepatocyte-specific overexpression of NIK resulted in higher glucagon responses and HGP. In isolated mouse livers and primary hepatocytes, NIK also promoted glucagon action and glucose production, at least in part by increasing cAMP response element-binding (CREB) stability. Therefore, overactivation of liver NIK in obesity promotes hyperglycemia and glucose intolerance by increasing the hyperglycemic response to glucagon and other factors that activate CREB.

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Figure 1: NIK is overactivated in the livers of mice with obesity.
Figure 2: Inhibition of NIK in the liver decreases hyperglycemia and glucose intolerance in mice with obesity.
Figure 3: Hepatocyte NIK regulates blood glucose concentrations and HGP.
Figure 4: NIK promotes the stimulation of glucose production by glucagon.
Figure 5: NIK mediates the enhancement of glucagon action induced by HFD and by TNF-α, hydrogen peroxide and palmitic acid.
Figure 6: NIK phosphorylates CREB and increases CREB stability.

References

  1. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Shoelson, S.E. & Goldfine, A.B. Getting away from glucose: fanning the flames of obesity-induced inflammation. Nat. Med. 15, 373–374 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Arkan, M.C. et al. IKK-β links inflammation to obesity-induced insulin resistance. Nat. Med. 11, 191–198 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat. Med. 11, 183–190 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Unger, R.H. & Cherrington, A.D. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J. Clin. Invest. 122, 4–12 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jiang, G. & Zhang, B.B. Glucagon and regulation of glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 284, E671–E678 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Denroche, H.C. et al. Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes 60, 1414–1423 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yu, X., Park, B.H., Wang, M.Y., Wang, Z.V. & Unger, R.H. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc. Natl. Acad. Sci. USA 105, 14070–14075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lee, Y., Wang, M.Y., Du, X.Q., Charron, M.J. & Unger, R.H. Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 60, 391–397 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cummings, B.P. et al. Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. Proc. Natl. Acad. Sci. USA 108, 14670–14675 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Maruyama, H., Hisatomi, A., Orci, L., Grodsky, G.M. & Unger, R.H. Insulin within islets is a physiologic glucagon release inhibitor. J. Clin. Invest. 74, 2296–2299 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Thu, Y.M. & Richmond, A. NF-κB inducing kinase: a key regulator in the immune system and in cancer. Cytokine Growth Factor Rev. 21, 213–226 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sun, S.C. Non-canonical NF-κB signaling pathway. Cell Res. 21, 71–85 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Yin, L. et al. Defective lymphotoxin-β receptor-induced NF-κB transcriptional activity in NIK-deficient mice. Science 291, 2162–2165 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Murray, S.E. et al. NF-κB–inducing kinase plays an essential T cell–intrinsic role in graft-versus-host disease and lethal autoimmunity in mice. J. Clin. Invest. 121, 4775–4786 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ling, L., Cao, Z. & Goeddel, D.V. NF-κB–inducing kinase activates IKK-α by phosphorylation of Ser-176. Proc. Natl. Acad. Sci. USA 95, 3792–3797 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xiao, G., Fong, A. & Sun, S.C. Induction of p100 processing by NF-κB–inducing kinase involves docking IκB kinase α (IKKα) to p100 and IKKα-mediated phosphorylation. J. Biol. Chem. 279, 30099–30105 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Xiao, G., Harhaj, E.W. & Sun, S.C. NF-κB–inducing kinase regulates the processing of NF-κB2 p100. Mol. Cell 7, 401–409 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Malinin, N.L., Boldin, M.P., Kovalenko, A.V. & Wallach, D. MAP3K-related kinase involved in NF-κB induction by TNF, CD95 and IL-1. Nature 385, 540–544 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Ninomiya-Tsuji, J. et al. The kinase TAK1 can activate the NIK-I κB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398, 252–256 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Sasaki, Y. et al. NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R–mediated survival signals in B cells. Proc. Natl. Acad. Sci. USA 105, 10883–10888 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Herzig, S. et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179–183 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Zhou, X.Y. et al. Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein. Nat. Med. 10, 633–637 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Koo, S.H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. He, L. et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137, 635–646 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yoon, J.C. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Liao, G., Zhang, M., Harhaj, E.W. & Sun, S.C. Regulation of the NF-κB–inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J. Biol. Chem. 279, 26243–26250 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Vallabhapurapu, S. et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling. Nat. Immunol. 9, 1364–1370 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zarnegar, B.J. et al. Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat. Immunol. 9, 1371–1378 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Duan, C., Yang, H., White, M.F. & Rui, L. Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. Mol. Cell. Biol. 24, 7435–7443 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Aoki, K. et al. Dehydroepiandrosterone suppresses the elevated hepatic glucose-6-phosphatase and fructose-1,6-bisphosphatase activities in C57BL/Ksj-db/db mice: comparison with troglitazone. Diabetes 48, 1579–1585 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Ren, D. et al. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. J. Clin. Invest. 117, 397–406 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhou, Y., Jiang, L. & Rui, L. Identification of MUP1 as a regulator for glucose and lipid metabolism in mice. J. Biol. Chem. 284, 11152–11159 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Huang, W., Dedousis, N., Bhatt, B.A. & O'Doherty, R.M. Impaired activation of phosphatidylinositol 3-kinase by leptin is a novel mechanism of hepatic leptin resistance in diet-induced obesity. J. Biol. Chem. 279, 21695–21700 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Cho, K.W., Zhou, Y., Sheng, L. & Rui, L. Lipocalin-13 regulates glucose metabolism by both insulin-dependent and insulin-independent mechanisms. Mol. Cell. Biol. 31, 450–457 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Sheng, L., Cho, K.W., Zhou, Y., Shen, H. & Rui, L. Lipocalin 13 protein protects against hepatic steatosis by both inhibiting lipogenesis and stimulating fatty acid β-oxidation. J. Biol. Chem. 286, 38128–38135 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank H. Su, Z. Li, C. Duan, D. Morris and S. Wang for assistance and discussion. We thank R. Schreiber (Washington University School of Medicine, St. Louis, Missouri) for providing NIK knockout mice and K. Rajewsky (Immune Disease Institute, Harvard Medical School, Boston, Massachusetts) for providing STOP-NIK mice. Generation of the NIK knockout mice was supported by Amgen Inc., Thousand Oaks, California. This study was supported by grants DK 065122 and DK073601 from the US National Institutes of Health (NIH) and by research award 1-09-RA-156 from the American Diabetes Association. This work used the cores supported by the Michigan Diabetes Research and Training Center (funded by NIH 5P60 DK20572), the University of Michigan's Cancer Center (funded by NIH 5 P30 CA46592), the University of Michigan Nathan Shock Center (funded by NIH P30AG013283) and the University of Michigan Gut Peptide Research Center (funded by NIH DK34933).

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Authors and Affiliations

  1. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Liang Sheng, Yingjiang Zhou, Zheng Chen, Decheng Ren, Kae Won Cho, Lin Jiang, Hong Shen & Liangyou Rui

  2. Laboratory for Stem Cell Biology, Riken Center for Developmental Biology, Kobe, Japan

    Yoshiteru Sasaki

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Contributions

L.R. and L.S. designed the experiments and prepared the manuscript. L.S., Y.Z., Z.C., D.R., K.W.C., L.J. and H.S. performed experiments. Y.S. generated the STOP-NIK mice.

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Correspondence to Liangyou Rui.

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Sheng, L., Zhou, Y., Chen, Z. et al. NF-κB–inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action. Nat Med 18, 943–949 (2012). https://doi.org/10.1038/nm.2756

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