Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

TY - JOUR

T1 - Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

AU - Malle, Elisabeth K.

AU - Zammit, Nathan W.

AU - Walters, Stacey N.

AU - Koay, Yen Chin

AU - Wu, Jianmin

AU - Tan, Bernice M.

AU - Villanueva, Jeanette E.

AU - Brink, Robert

AU - Loudovaris, Tom

AU - Cantley, James

AU - McAlpine, Shelli R.

AU - Hesselson, Daniel

AU - Grey, Shane T.

PY - 2015/6/29

Y1 - 2015/6/29

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84964697787

U2 - 10.1084/jem.20150218

DO - 10.1084/jem.20150218

M3 - Article

C2 - 26122662

AN - SCOPUS:84964697787

SN - 0022-1007

VL - 212

SP - 1239

EP - 1254

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 8

ER -