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Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2

Amyloid-β (Aβ), a natural product of cell metabolism, plays a key role in the pathogenesis of Alzheimer’s disease (AD). Epidemiological studies indicate patients with AD have an increased risk of developing type 2 diabetes mellitus (T2DM). Aβ can induce insulin resistance in cultured hepatocytes by...

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Autores principales: Zhang, Yi, Zhou, Ben, Deng, Bo, Zhang, Fang, Wu, Jingxia, Wang, Yuangao, Le, Yingying, Zhai, Qiwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609589/
https://www.ncbi.nlm.nih.gov/pubmed/23223021
http://dx.doi.org/10.2337/db12-0670
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author Zhang, Yi
Zhou, Ben
Deng, Bo
Zhang, Fang
Wu, Jingxia
Wang, Yuangao
Le, Yingying
Zhai, Qiwei
author_facet Zhang, Yi
Zhou, Ben
Deng, Bo
Zhang, Fang
Wu, Jingxia
Wang, Yuangao
Le, Yingying
Zhai, Qiwei
author_sort Zhang, Yi
collection PubMed
description Amyloid-β (Aβ), a natural product of cell metabolism, plays a key role in the pathogenesis of Alzheimer’s disease (AD). Epidemiological studies indicate patients with AD have an increased risk of developing type 2 diabetes mellitus (T2DM). Aβ can induce insulin resistance in cultured hepatocytes by activating the JAK2/STAT3/SOCS-1 signaling pathway. Amyloid precursor protein and presenilin 1 double-transgenic AD mouse models with increased circulating Aβ level show impaired glucose/insulin tolerance and hepatic insulin resistance. However, whether Aβ induces hepatic insulin resistance in vivo is still unclear. Here we show C57BL/6J mice intraperitoneally injected with Aβ42 exhibit increased fasting blood glucose level, impaired insulin tolerance, and hepatic insulin signaling. Moreover, the APPswe/PSEN1dE9 AD model mice intraperitoneally injected with anti-Aβ neutralizing antibodies show decreased fasting blood glucose level and improved insulin sensitivity. Injection of Aβ42 activates hepatic JAK2/STAT3/SOCS-1 signaling, and neutralization of Aβ in APPswe/PSEN1dE9 mice inhibits liver JAK2/STAT3/SOCS-1 signaling. Furthermore, knockdown of hepatic JAK2 by tail vein injection of adenovirus inhibits JAK2/STAT3/SOCS-1 signaling and improves glucose/insulin tolerance and hepatic insulin sensitivity in APPswe/PSEN1dE9 mice. Our results demonstrate that Aβ induces hepatic insulin resistance in vivo via JAK2, suggesting that inhibition of Aβ signaling is a new strategy toward resolving insulin resistance and T2DM.
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spelling pubmed-36095892014-04-01 Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2 Zhang, Yi Zhou, Ben Deng, Bo Zhang, Fang Wu, Jingxia Wang, Yuangao Le, Yingying Zhai, Qiwei Diabetes Original Research Amyloid-β (Aβ), a natural product of cell metabolism, plays a key role in the pathogenesis of Alzheimer’s disease (AD). Epidemiological studies indicate patients with AD have an increased risk of developing type 2 diabetes mellitus (T2DM). Aβ can induce insulin resistance in cultured hepatocytes by activating the JAK2/STAT3/SOCS-1 signaling pathway. Amyloid precursor protein and presenilin 1 double-transgenic AD mouse models with increased circulating Aβ level show impaired glucose/insulin tolerance and hepatic insulin resistance. However, whether Aβ induces hepatic insulin resistance in vivo is still unclear. Here we show C57BL/6J mice intraperitoneally injected with Aβ42 exhibit increased fasting blood glucose level, impaired insulin tolerance, and hepatic insulin signaling. Moreover, the APPswe/PSEN1dE9 AD model mice intraperitoneally injected with anti-Aβ neutralizing antibodies show decreased fasting blood glucose level and improved insulin sensitivity. Injection of Aβ42 activates hepatic JAK2/STAT3/SOCS-1 signaling, and neutralization of Aβ in APPswe/PSEN1dE9 mice inhibits liver JAK2/STAT3/SOCS-1 signaling. Furthermore, knockdown of hepatic JAK2 by tail vein injection of adenovirus inhibits JAK2/STAT3/SOCS-1 signaling and improves glucose/insulin tolerance and hepatic insulin sensitivity in APPswe/PSEN1dE9 mice. Our results demonstrate that Aβ induces hepatic insulin resistance in vivo via JAK2, suggesting that inhibition of Aβ signaling is a new strategy toward resolving insulin resistance and T2DM. American Diabetes Association 2013-04 2013-03-14 /pmc/articles/PMC3609589/ /pubmed/23223021 http://dx.doi.org/10.2337/db12-0670 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Research
Zhang, Yi
Zhou, Ben
Deng, Bo
Zhang, Fang
Wu, Jingxia
Wang, Yuangao
Le, Yingying
Zhai, Qiwei
Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2
title Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2
title_full Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2
title_fullStr Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2
title_full_unstemmed Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2
title_short Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2
title_sort amyloid-β induces hepatic insulin resistance in vivo via jak2
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609589/
https://www.ncbi.nlm.nih.gov/pubmed/23223021
http://dx.doi.org/10.2337/db12-0670
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