Abrogation of adenosine A1 receptor signalling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses
| Autor: | Robert A. Harris, Monica Sandberg, Christa Zollbrecht, Xing-Mei Zhang, Maria Peleli, Ming Liu, Ting Yang, Michael Hezel, Leif Jansson, En Yin Lai, A. Erik G. Persson, Bertil B. Fredholm, Xiang Gao, Mattias Carlström |
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| Rok vydání: | 2015 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male Aging medicine.medical_specialty Endocrinology Diabetes and Metabolism medicine.medical_treatment Adipose tissue Proinflammatory cytokine Islets of Langerhans Mice Insulin resistance Internal medicine Glucose Intolerance Internal Medicine medicine Animals Insulin Inflammation Mice Knockout geography Membrane Glycoproteins NADPH oxidase geography.geographical_feature_category biology Receptor Adenosine A1 Angiotensin II Leptin NADPH Oxidases medicine.disease Islet Mice Inbred C57BL Oxidative Stress Metabolism Endocrinology Adipose Tissue Regional Blood Flow NADPH Oxidase 2 Body Composition biology.protein Cytokines Female Insulin Resistance Signal Transduction |
| Zdroj: | Diabetologia. 58:1610-1620 |
| ISSN: | 1432-0428 0012-186X |
| DOI: | 10.1007/s00125-015-3570-3 |
| Popis: | 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. Age-matched young and aged A 1 (also known as Adora1)-knockout (A 1 −/−) 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. 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 −/− 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 −/− 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 −/− mice, including enhanced NADPH oxidase-derived O2 − 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. 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. |
| Databáze: | OpenAIRE |
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