Liver NF-κB-Inducing Kinase Promotes Liver Steatosis and Glucose Counterregulation in Male Mice With Obesity.

Obesity is associated with chronic inflammation and liver steatoses. Numerous proinflammatory cytokines have been reported to regulate liver glucose and lipid metabolism, thus contributing to the pathogenesis of liver steatosis and/or metabolic dysfunction. Nuclear factor-κB-inducing kinase (NIK) is stimulated by many cytokines and mediates activation of the noncanonical nuclear factor-κB pathway. We previously reported that liver NIK is aberrantly activated in obesity; inactivation of NIK by overexpressing dominant negative NIK(KA) suppresses hepatic glucose production. In the present study, we generated conditional NIK knockout mice using the Cre/loxp system. Mice with hepatocyte-specific or hematopoietic lineage-specific deletion of NIK were normal with either normal chow diet or high-fat diet (HFD) conditions. In contrast, deletion of NIK in the liver, including both hepatocytes and immune cells, protected against HFD-induced liver steatosis and attenuated hepatic glucose production. Mechanistically, deletion of liver NIK suppressed liver inflammation and lipogenic programs, thus contributing to protection against liver steatosis. Liver NIK also downregulated cyclic nucleotide phosphodiesterases, thereby augmenting the cyclic adenosine monophosphate/protein kinase A pathway and glucagon-stimulated hepatic glucose production. Together, our data suggest that NIK pathways in both hepatocytes and immune cells act in concert to promote liver steatosis and glucose production in the setting of obesity.