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SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression

Adipocyte dysfunction correlates with the development of diabetes. Here we show that mice with a adipocyte-specific deletion of the SUMO-specific protease SENP1 gene develop symptoms of type-1 diabetes mellitus (T1DM), including hyperglycaemia and glucose intolerance with mild insulin resistance. Pe...

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Autores principales: Shao, Lan, Zhou, Huanjiao Jenny, Zhang, Haifeng, Qin, Lingfeng, Hwa, John, Yun, Zhong, Ji, Weidong, Min, Wang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662081/
https://www.ncbi.nlm.nih.gov/pubmed/26596471
http://dx.doi.org/10.1038/ncomms9917
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author Shao, Lan
Zhou, Huanjiao Jenny
Zhang, Haifeng
Qin, Lingfeng
Hwa, John
Yun, Zhong
Ji, Weidong
Min, Wang
author_facet Shao, Lan
Zhou, Huanjiao Jenny
Zhang, Haifeng
Qin, Lingfeng
Hwa, John
Yun, Zhong
Ji, Weidong
Min, Wang
author_sort Shao, Lan
collection PubMed
description Adipocyte dysfunction correlates with the development of diabetes. Here we show that mice with a adipocyte-specific deletion of the SUMO-specific protease SENP1 gene develop symptoms of type-1 diabetes mellitus (T1DM), including hyperglycaemia and glucose intolerance with mild insulin resistance. Peri-pancreatic adipocytes from SENP1-deficient mice exhibit heightened NF-κB activity and production of proinflammatory cytokines, which induce CCL5 expression in adjacent pancreatic islets and direct cytotoxic effects on pancreatic islets. Mechanistic studies show that SENP1 deletion in adipocytes enhances SUMOylation of the NF-κB essential molecule, NEMO, at lysine 277/309, leading to increased NF-κB activity, cytokine production and pancreatic inflammation. We further show that NF-κB inhibitors could inhibit pre-diabetic cytokine production, β-cell damages and ameliorate the T1DM phenotype in SENP1-deficient mice. Feeding a high-fat diet augments both type-1 and type-2 diabetes phenotypes in SENP1-deficient mice, consistent with the effects on adipocyte-derived NF-κB and cytokine signalling. Our study reveals previously unrecognized mechanism regulating the onset and progression of T1DM associated with adipocyte dysfunction.
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spelling pubmed-46620812015-12-17 SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression Shao, Lan Zhou, Huanjiao Jenny Zhang, Haifeng Qin, Lingfeng Hwa, John Yun, Zhong Ji, Weidong Min, Wang Nat Commun Article Adipocyte dysfunction correlates with the development of diabetes. Here we show that mice with a adipocyte-specific deletion of the SUMO-specific protease SENP1 gene develop symptoms of type-1 diabetes mellitus (T1DM), including hyperglycaemia and glucose intolerance with mild insulin resistance. Peri-pancreatic adipocytes from SENP1-deficient mice exhibit heightened NF-κB activity and production of proinflammatory cytokines, which induce CCL5 expression in adjacent pancreatic islets and direct cytotoxic effects on pancreatic islets. Mechanistic studies show that SENP1 deletion in adipocytes enhances SUMOylation of the NF-κB essential molecule, NEMO, at lysine 277/309, leading to increased NF-κB activity, cytokine production and pancreatic inflammation. We further show that NF-κB inhibitors could inhibit pre-diabetic cytokine production, β-cell damages and ameliorate the T1DM phenotype in SENP1-deficient mice. Feeding a high-fat diet augments both type-1 and type-2 diabetes phenotypes in SENP1-deficient mice, consistent with the effects on adipocyte-derived NF-κB and cytokine signalling. Our study reveals previously unrecognized mechanism regulating the onset and progression of T1DM associated with adipocyte dysfunction. Nature Pub. Group 2015-11-24 /pmc/articles/PMC4662081/ /pubmed/26596471 http://dx.doi.org/10.1038/ncomms9917 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Shao, Lan
Zhou, Huanjiao Jenny
Zhang, Haifeng
Qin, Lingfeng
Hwa, John
Yun, Zhong
Ji, Weidong
Min, Wang
SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression
title SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression
title_full SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression
title_fullStr SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression
title_full_unstemmed SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression
title_short SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression
title_sort senp1-mediated nemo desumoylation in adipocytes limits inflammatory responses and type-1 diabetes progression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662081/
https://www.ncbi.nlm.nih.gov/pubmed/26596471
http://dx.doi.org/10.1038/ncomms9917
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