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Nuclear factor ?B-inducing kinase activation as a mechanism of pancreatic ? cell failure in obesity.

ABSTRACT: The nuclear factor ?B (NF-?B) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic ? cell dysfunction in the metabolic syndrome. Whereas canonical NF-?B signaling is well studied, there is little information on the divergent noncanonical NF-?B pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-?B-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of ? 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-?B components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-?B ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive ? cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-?B transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to ? cell failure. These studies reveal that NIK contributes a central mechanism for ? cell failure in diet-induced obesity.

SUBMITTER: Malle EK

PROVIDER: S-EPMC4516791 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Malle Elisabeth K EK Zammit Nathan W NW Walters Stacey N SN Koay Yen Chin YC Wu Jianmin J Tan Bernice M BM Villanueva Jeanette E JE Brink Robert R Loudovaris Tom T Cantley James J McAlpine Shelli R SR Hesselson Daniel D Grey Shane T ST

The Journal of experimental medicine 20150629 8

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 ...[more]

PMID: 26122662

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Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, 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 non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB 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 non-canonical NF-κB 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. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).

Dataset Information

Nuclear factor ?B-inducing kinase activation as a mechanism of pancreatic ? cell failure in obesity.

Publications

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

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