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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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).
The authors declare no competing financial interests.
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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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