Title:	Nuclear factor kappa B-inducing kinase activation as a mechanism of pancreatic beta cell failure in obesity
Authors:	Malle, EK Zammit, NW Walters, SN Koay, YC Wu, JM Tan, BM Villanueva, JE Brink, R Loudovaris, T Cantley, J McAlpine, SR Hesselson, D Grey, ST
Issue Year:	2015
Publisher	ROCKEFELLER UNIV PRESS
Series	J. Exp. Med.:
Abstract	The nuclear factor kappa B (NF-kappa B) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. Whereas canonical NF-kappa B signaling is well studied, there is little information on the divergent noncanonical NF-kappa B pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-kappa B-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of beta 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-kappa B components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-kappa B ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-kappa B transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity.
URI:	https://publications.svi.edu.au/publications/2223
Other Identifiers	10.1084/jem.20150218
Publication type	Article