Cargando…

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

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-κ...

Descripción completa

Detalles Bibliográficos
Autores principales: Malle, Elisabeth K., Zammit, Nathan W., Walters, Stacey N., Koay, Yen Chin, Wu, Jianmin, Tan, Bernice M., Villanueva, Jeanette E., Brink, Robert, Loudovaris, Tom, Cantley, James, McAlpine, Shelli R., Hesselson, Daniel, Grey, Shane T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516791/
https://www.ncbi.nlm.nih.gov/pubmed/26122662
http://dx.doi.org/10.1084/jem.20150218
_version_ 1782383093491957760
author Malle, Elisabeth K.
Zammit, Nathan W.
Walters, Stacey N.
Koay, Yen Chin
Wu, Jianmin
Tan, Bernice M.
Villanueva, Jeanette E.
Brink, Robert
Loudovaris, Tom
Cantley, James
McAlpine, Shelli R.
Hesselson, Daniel
Grey, Shane T.
author_facet Malle, Elisabeth K.
Zammit, Nathan W.
Walters, Stacey N.
Koay, Yen Chin
Wu, Jianmin
Tan, Bernice M.
Villanueva, Jeanette E.
Brink, Robert
Loudovaris, Tom
Cantley, James
McAlpine, Shelli R.
Hesselson, Daniel
Grey, Shane T.
author_sort Malle, Elisabeth K.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4516791
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-45167912016-01-27 Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity Malle, Elisabeth K. Zammit, Nathan W. Walters, Stacey N. Koay, Yen Chin Wu, Jianmin Tan, Bernice M. Villanueva, Jeanette E. Brink, Robert Loudovaris, Tom Cantley, James McAlpine, Shelli R. Hesselson, Daniel Grey, Shane T. J Exp Med Article 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. The Rockefeller University Press 2015-07-27 /pmc/articles/PMC4516791/ /pubmed/26122662 http://dx.doi.org/10.1084/jem.20150218 Text en © 2015 Malle et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Malle, Elisabeth K.
Zammit, Nathan W.
Walters, Stacey N.
Koay, Yen Chin
Wu, Jianmin
Tan, Bernice M.
Villanueva, Jeanette E.
Brink, Robert
Loudovaris, Tom
Cantley, James
McAlpine, Shelli R.
Hesselson, Daniel
Grey, Shane T.
Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
title Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
title_full Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
title_fullStr Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
title_full_unstemmed Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
title_short Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
title_sort nuclear factor κb–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516791/
https://www.ncbi.nlm.nih.gov/pubmed/26122662
http://dx.doi.org/10.1084/jem.20150218
work_keys_str_mv AT malleelisabethk nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT zammitnathanw nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT waltersstaceyn nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT koayyenchin nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT wujianmin nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT tanbernicem nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT villanuevajeanettee nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT brinkrobert nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT loudovaristom nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT cantleyjames nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT mcalpineshellir nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT hesselsondaniel nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity
AT greyshanet nuclearfactorkbinducingkinaseactivationasamechanismofpancreaticbcellfailureinobesity