Abrogation of adenosine A1 receptor signalling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses
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- 作者：Ting Yang ; Xiang Gao ; Monica Sandberg ; Christa Zollbrecht ; Xing-Mei Zhang…
- 关键词：Insulin sensitivity and resistance ; Islets ; Metabolic physiology in vivo ; Metabolic syndrome ; Oxidative stress ; Type 2 diabetes ; Visceral adipose tissue
- 刊名：Diabetologia
- 出版年：2015
- 出版时间：July 2015
- 年：2015
- 卷：58
- 期：7
- 页码：1610-1620
- 全文大小：1,990 KB
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Xiang Gao (2)
Monica Sandberg (2)
Christa Zollbrecht (1)
Xing-Mei Zhang (3)
Michael Hezel (1)
Ming Liu (1)
Maria Peleli (1)
En-Yin Lai (4)
Robert A. Harris (3)
A. Erik G. Persson (2)
Bertil B. Fredholm (1)
Leif Jansson (2)
Mattias Carlstr?m (1) (4)
1. Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz V?g 2, SE-171 77, Stockholm, Sweden
2. Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
3. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
4. Division of Nephrology & Hypertension, and Hypertension, Kidney & Vascular Research Center, Georgetown University, Washington, DC, USA - 刊物类别：Medicine
- 刊物主题：Medicine & Public Health
Internal Medicine
Metabolic Diseases
Human Physiology - 出版者：Springer Berlin / Heidelberg
- ISSN：1432-0428
文摘
Aims/hypothesis Adenosine is an important regulator of metabolism; however, the role of the A1 receptor during ageing and obesity is unclear. The aim of this study was to investigate the effects of A1 signalling in modulating metabolic function during ageing. Methods Age-matched young and aged A 1 (also known as Adora1)-knockout (A 1 ??/sup>) and wild-type (A 1 +/+) mice were used. Metabolic regulation was evaluated by body composition, and glucose and insulin tolerance tests. Isolated islets and islet arterioles were used to detect islet endocrine and vascular function. Oxidative stress and inflammation status were measured in metabolic organs and systemically. Results Advanced age was associated with both reduced glucose clearance and insulin sensitivity, as well as increased visceral adipose tissue (VAT) in A 1 +/+ compared with A 1 ??/sup> mice. Islet morphology and insulin content were similar between genotypes, but relative changes in in vitro insulin release following glucose stimulation were reduced in aged A 1 +/+ compared with A 1 ??/sup> mice. Islet arteriolar responses to angiotensin II were stronger in aged A 1 +/+ mice, this being associated with increased NADPH oxidase activity. Ageing resulted in multiple changes in A 1 +/+ compared with A 1 ??/sup> mice, including enhanced NADPH oxidase-derived O2 ?/sup> formation and NADPH oxidase isoform 2 (Nox2) protein expression in pancreas and VAT; elevated levels of circulating insulin, leptin and proinflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-12); and accumulation of CD4+ T cells in VAT. This was associated with impaired insulin signalling in VAT from aged A 1 +/+ mice. Conclusions/interpretation These studies emphasise that A1 receptors regulate metabolism and islet endocrine and vascular functions during ageing, including via the modulation of oxidative stress and inflammatory responses, among other things.