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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
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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 |
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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 |
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