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Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity

Obesity is associated with low-grade inflammation that leads to insulin resistance and type 2 diabetes via Toll-like Receptor (TLR) and TNF-family cytokine receptor (TNFR) signaling pathways. Ubc13 is an ubiquitin-conjugating enzyme responsible for non-canonical K63-linked polyubiquitination of TNF...

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Autores principales: Joo, Erina, Fukushima, Toru, Harada, Norio, Reed, John C., Matsuzawa, Shu-ichi, Inagaki, Nobuya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086849/
https://www.ncbi.nlm.nih.gov/pubmed/27796312
http://dx.doi.org/10.1038/srep35983
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author Joo, Erina
Fukushima, Toru
Harada, Norio
Reed, John C.
Matsuzawa, Shu-ichi
Inagaki, Nobuya
author_facet Joo, Erina
Fukushima, Toru
Harada, Norio
Reed, John C.
Matsuzawa, Shu-ichi
Inagaki, Nobuya
author_sort Joo, Erina
collection PubMed
description Obesity is associated with low-grade inflammation that leads to insulin resistance and type 2 diabetes via Toll-like Receptor (TLR) and TNF-family cytokine receptor (TNFR) signaling pathways. Ubc13 is an ubiquitin-conjugating enzyme responsible for non-canonical K63-linked polyubiquitination of TNF receptor-associated factor (TRAF)-family adapter proteins involved in TLR and TNFR pathways. However, the relationship between Ubc13 and metabolic disease remains unclear. In this study, we investigated the role of Ubc13 in insulin resistance and high-fat diet (HFD)-induced obesity. We compared wild-type (WT) and Ubc13 haploinsufficient (ubc13(+/−)) mice under normal diet (ND) and HFD, since homozygous knockout mice (ubc13(−/−)) are embryonic lethal. Male and female ubc13(+/−) mice were protected against age-related insulin resistance under ND and HFD compared to WT mice. Interestingly, only female ubc13(+/−) mice were protected against HFD-induced obesity and hepatic steatosis. Moreover, only female HFD-fed ubc13(+/−) mice showed lower expression of inflammatory cytokines that was secondary to reduction in weight gain not present in the other groups. In summary, our results indicate that suppression of Ubc13 activity may play a metabolic role independent of its inflammatory function. Thus, Ubc13 could represent a therapeutic target for insulin resistance, diet-induced obesity, and associated metabolic dysfunctions.
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spelling pubmed-50868492016-11-04 Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity Joo, Erina Fukushima, Toru Harada, Norio Reed, John C. Matsuzawa, Shu-ichi Inagaki, Nobuya Sci Rep Article Obesity is associated with low-grade inflammation that leads to insulin resistance and type 2 diabetes via Toll-like Receptor (TLR) and TNF-family cytokine receptor (TNFR) signaling pathways. Ubc13 is an ubiquitin-conjugating enzyme responsible for non-canonical K63-linked polyubiquitination of TNF receptor-associated factor (TRAF)-family adapter proteins involved in TLR and TNFR pathways. However, the relationship between Ubc13 and metabolic disease remains unclear. In this study, we investigated the role of Ubc13 in insulin resistance and high-fat diet (HFD)-induced obesity. We compared wild-type (WT) and Ubc13 haploinsufficient (ubc13(+/−)) mice under normal diet (ND) and HFD, since homozygous knockout mice (ubc13(−/−)) are embryonic lethal. Male and female ubc13(+/−) mice were protected against age-related insulin resistance under ND and HFD compared to WT mice. Interestingly, only female ubc13(+/−) mice were protected against HFD-induced obesity and hepatic steatosis. Moreover, only female HFD-fed ubc13(+/−) mice showed lower expression of inflammatory cytokines that was secondary to reduction in weight gain not present in the other groups. In summary, our results indicate that suppression of Ubc13 activity may play a metabolic role independent of its inflammatory function. Thus, Ubc13 could represent a therapeutic target for insulin resistance, diet-induced obesity, and associated metabolic dysfunctions. Nature Publishing Group 2016-10-31 /pmc/articles/PMC5086849/ /pubmed/27796312 http://dx.doi.org/10.1038/srep35983 Text en Copyright © 2016, The Author(s) 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
Joo, Erina
Fukushima, Toru
Harada, Norio
Reed, John C.
Matsuzawa, Shu-ichi
Inagaki, Nobuya
Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity
title Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity
title_full Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity
title_fullStr Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity
title_full_unstemmed Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity
title_short Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity
title_sort ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086849/
https://www.ncbi.nlm.nih.gov/pubmed/27796312
http://dx.doi.org/10.1038/srep35983
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