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.
Date: 2015
Source: The Journal of experimental medicine   212(8): 1239-54 (Journal)
Registered Authors: Hesselson, Daniel
Keywords: none
MeSH Terms:
  • Animals
  • Blotting, Western
  • DNA Primers/genetics
  • Humans
  • Immunohistochemistry
  • Insulin
  • Insulin-Secreting Cells/enzymology*
  • Insulin-Secreting Cells/pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity/enzymology*
  • Obesity/pathology
  • Protein Serine-Threonine Kinases/metabolism*
  • Signal Transduction/physiology*
  • Zebrafish
PubMed: 26122662 Full text @ J. Exp. Med.
The 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.