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

Nature Medicine
Liang ShengLiangyou Rui

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 promot...Continue Reading

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Citations

Apr 3, 2014·Comprehensive Physiology·Liangyou Rui
Feb 26, 2016·Molecular Metabolism·Zheng ChenLiangyou Rui
Jul 1, 2015·The Journal of Experimental Medicine·Elisabeth K MalleShane T Grey
Sep 23, 2014·Neurobiology of Disease·Kelly T DineleyLarry Denner
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Mar 27, 2019·Journal of Cellular Physiology·Chuanfeng TangLiang Sheng
Aug 29, 2013·American Journal of Physiology. Endocrinology and Metabolism·Liang ShengLiangyou Rui
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Methods Mentioned

BETA
ubiquitination
protein assay

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