title: NF-κB–inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action.
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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Sheng
authors.forename: Yingjiang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Decheng
authors.initials: D
authors.lastname: Ren
authors.forename: Kae Won
authors.initials: KW
authors.lastname: Cho
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Liangyou
authors.initials: L
authors.lastname: Rui
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000209:etiology*; D006943:Hyperglycemia / Q000209:etiology*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000502:physiology; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D005934:Glucagon; D005947:Glucose; D008869:Microtubule-Associated Proteins; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C492004:Creb1 protein, mouse; C491893:Mtap6 protein, mouse