Nuclear factor ÎºBâinducing kinase activation as a mechanism of pancreatic Î² cell failure in obesity
The nuclear factor ÎºB (NF-ÎºB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic Î² cell dysfunction in the metabolic syndrome. Whereas canonical NF-ÎºB signaling is well studied, there is little information on the divergent noncanonical NF-ÎºB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-ÎºBâinducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of Î² 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-ÎºB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-ÎºB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive Î² cellâintrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-ÎºB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to Î² cell failure. These studies reveal that NIK contributes a central mechanism for Î² cell failure in diet-induced obesity.
|Authors||Malle, E.K.; Zammit, N.W.; Walters, S.N.; Koay, Y.C.; Wu, J.; Tan, B.M.; Villanueva, J.; Brink, R.; Loudovaris, T.; Cantley, J.; McAlpine, S.R.; Hesselson, D.; Grey, S.T.|
|Responsible Garvan Author|
|Publisher Name||JOURNAL OF EXPERIMENTAL MEDICINE|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/26122662|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12914|