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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.

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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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