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

The canonical IKKβ/NF-κB1 pathway has been well documented to promote insulin resistance; however, the noncanonical NIK/NF-κB2 pathway is poorly understood in obesity. Additionally, the contribution of counterregulatory hormones, particularly glucagon, to hyperglycemia in obesity remains 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 NIK decreased glucagon responses and hepatic glucose production (HGP). Obesity is associated with increased glucagon responses, and liver-specific inhibition of NIK decreased glucagon responses and HGP and protected against hyperglycemia and glucose intolerance. Conversely, hepatocyte-specific overexpression of NIK increased glucagon responses and HGP. In isolated livers and primary hepatocytes, NIK also promoted glucagon action and glucose production, at least in part by increasing 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.