Endothelial adenosine kinase deficiency ameliorates diet-induced insulin resistance

Jiean Xu, Qiuhua Yang, Xiaoyu Zhang, Zhiping Liu, Yapeng Cao, Lina Wang, Yaqi Zhou, Xianqiu Zeng, Qian Ma, Yiming Xu, Yong Wang, Lei Huang, Zhen Han, Tao Wang, David Stepp, Zsolt Bagi, Chaodong Wu, Mei Hong, Yuqing Huo

Research output: Contribution to journalArticle

Abstract

Insulin resistance-related disorders are associated with endothelial dysfunction. Accumulating evidence has suggested a role for adenosine signaling in the regulation of endothelial function. Here, we identified a crucial role of endothelial adenosine kinase (ADK) in the regulation of insulin resistance. Feeding mice with a high-fat diet (HFD) markedly enhanced the expression of endothelial Adk. Ablation of endothelial Adk in HFD-fed mice improved glucose tolerance and insulin sensitivity and decreased hepatic steatosis, adipose inflammation and adiposity, which were associated with improved arteriole vasodilation, decreased inflammation and increased adipose angiogenesis. Mechanistically, ADK inhibition or knockdown in human umbilical vein endothelial cells (HUVECs) elevated intracellular adenosine level and increased endothelial nitric oxide synthase (NOS3) activity, resulting in an increase in nitric oxide (NO) production. Antagonism of adenosine receptor A2b abolished ADK-knockdown-enhanced NOS3 expression in HUVECs. Additionally, increased phosphorylation of NOS3 in ADK-knockdown HUVECs was regulated by an adenosine receptor-independent mechanism. These data suggest that Adk-deficiency-elevated intracellular adenosine in endothelial cells ameliorates diet-induced insulin resistance and metabolic disorders, and this is associated with an enhancement of NO production caused by increased NOS3 expression and activation. Therefore, ADK is a potential target for the prevention and treatment of metabolic disorders associated with insulin resistance.

Original languageEnglish (US)
Pages (from-to)159-172
Number of pages14
JournalThe Journal of endocrinology
Volume242
Issue number2
DOIs
StatePublished - Aug 1 2019

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Adenosine Kinase
Insulin Resistance
Diet
Human Umbilical Vein Endothelial Cells
Adenosine
Purinergic P1 Receptors
High Fat Diet
Nitric Oxide
Inflammation
Nitric Oxide Synthase Type III
Adiposity
Arterioles
Vasodilation
Endothelial Cells
Phosphorylation
Glucose
Liver

Keywords

  • adenosine kinase
  • endothelium
  • insulin resistance
  • nitric oxide
  • obesity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Endothelial adenosine kinase deficiency ameliorates diet-induced insulin resistance. / Xu, Jiean; Yang, Qiuhua; Zhang, Xiaoyu; Liu, Zhiping; Cao, Yapeng; Wang, Lina; Zhou, Yaqi; Zeng, Xianqiu; Ma, Qian; Xu, Yiming; Wang, Yong; Huang, Lei; Han, Zhen; Wang, Tao; Stepp, David; Bagi, Zsolt; Wu, Chaodong; Hong, Mei; Huo, Yuqing.

In: The Journal of endocrinology, Vol. 242, No. 2, 01.08.2019, p. 159-172.

Research output: Contribution to journalArticle

Xu, J, Yang, Q, Zhang, X, Liu, Z, Cao, Y, Wang, L, Zhou, Y, Zeng, X, Ma, Q, Xu, Y, Wang, Y, Huang, L, Han, Z, Wang, T, Stepp, D, Bagi, Z, Wu, C, Hong, M & Huo, Y 2019, 'Endothelial adenosine kinase deficiency ameliorates diet-induced insulin resistance', The Journal of endocrinology, vol. 242, no. 2, pp. 159-172. https://doi.org/10.1530/JOE-19-0126
Xu, Jiean ; Yang, Qiuhua ; Zhang, Xiaoyu ; Liu, Zhiping ; Cao, Yapeng ; Wang, Lina ; Zhou, Yaqi ; Zeng, Xianqiu ; Ma, Qian ; Xu, Yiming ; Wang, Yong ; Huang, Lei ; Han, Zhen ; Wang, Tao ; Stepp, David ; Bagi, Zsolt ; Wu, Chaodong ; Hong, Mei ; Huo, Yuqing. / Endothelial adenosine kinase deficiency ameliorates diet-induced insulin resistance. In: The Journal of endocrinology. 2019 ; Vol. 242, No. 2. pp. 159-172.
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AU - Xu, Jiean

AU - Yang, Qiuhua

AU - Zhang, Xiaoyu

AU - Liu, Zhiping

AU - Cao, Yapeng

AU - Wang, Lina

AU - Zhou, Yaqi

AU - Zeng, Xianqiu

AU - Ma, Qian

AU - Xu, Yiming

AU - Wang, Yong

AU - Huang, Lei

AU - Han, Zhen

AU - Wang, Tao

AU - Stepp, David

AU - Bagi, Zsolt

AU - Wu, Chaodong

AU - Hong, Mei

AU - Huo, Yuqing

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AB - Insulin resistance-related disorders are associated with endothelial dysfunction. Accumulating evidence has suggested a role for adenosine signaling in the regulation of endothelial function. Here, we identified a crucial role of endothelial adenosine kinase (ADK) in the regulation of insulin resistance. Feeding mice with a high-fat diet (HFD) markedly enhanced the expression of endothelial Adk. Ablation of endothelial Adk in HFD-fed mice improved glucose tolerance and insulin sensitivity and decreased hepatic steatosis, adipose inflammation and adiposity, which were associated with improved arteriole vasodilation, decreased inflammation and increased adipose angiogenesis. Mechanistically, ADK inhibition or knockdown in human umbilical vein endothelial cells (HUVECs) elevated intracellular adenosine level and increased endothelial nitric oxide synthase (NOS3) activity, resulting in an increase in nitric oxide (NO) production. Antagonism of adenosine receptor A2b abolished ADK-knockdown-enhanced NOS3 expression in HUVECs. Additionally, increased phosphorylation of NOS3 in ADK-knockdown HUVECs was regulated by an adenosine receptor-independent mechanism. These data suggest that Adk-deficiency-elevated intracellular adenosine in endothelial cells ameliorates diet-induced insulin resistance and metabolic disorders, and this is associated with an enhancement of NO production caused by increased NOS3 expression and activation. Therefore, ADK is a potential target for the prevention and treatment of metabolic disorders associated with insulin resistance.

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