|ZFIN ID: ZDB-PUB-150701-9|
Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
Malle, E.K., Zammit, N.W., Walters, S.N., Koay, Y.C., Wu, J., Tan, B.M., Villanueva, J.E., Brink, R., Loudovaris, T., Cantley, J., McAlpine, S.R., Hesselson, D., Grey, S.T.
|Source:||The Journal of experimental medicine 212(8): 1239-54 (Journal)|
|Registered Authors:||Hesselson, Daniel|
|PubMed:||26122662 Full text @ J. Exp. Med.|
Malle, E.K., Zammit, N.W., Walters, S.N., Koay, Y.C., Wu, J., Tan, B.M., Villanueva, J.E., Brink, R., Loudovaris, T., Cantley, J., McAlpine, S.R., Hesselson, D., Grey, S.T. (2015) Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity. The Journal of experimental medicine. 212(8):1239-54.
ABSTRACTThe nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity.