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Abrogation of adenosine A1 receptor signaling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Karolinska Institutet. (Department of Physiology & Pharmacology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Karolinska Institutet. (Department of Physiology & Pharmacology)
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(English)Manuscript (preprint) (Other academic)
Keyword [en]
type 2 diabetes, visceral adipose tissue, metabolic syndrome, insulin resistance, islet arterioles, inflammation and oxidative stress
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-230766OAI: oai:DiVA.org:uu-230766DiVA: diva2:741731
Note

Aims/hypothesis: Adenosine is an important regulator of metabolism, however, the role of A1receptor during aging and obesity is unclear. This study aimed at investigating the effects ofA1 signaling in modulating the metabolic function during aging. Methods: Age-matched young and aged A1-knockout (A1-/-) and wild-type (A1+/+) mice wereused. Metabolic regulation was evaluated by body composition, glucose and insulin tolerancetests. Isolated islets and islet arterioles were used to detect islet endocrine and vascularfunction. Oxidative stress and inflammation status were measured in metabolic organs andsystemically. Results: Advanced age was associated with reduced glucose clearance and insulin sensitivity, and increased white adipose tissue (VAT) in A1+/+ compared to A1-/- mice. Islet morphologyand insulin content were similar between genotypes, but relative changes in in vitro insulinrelease following glucose stimulation were reduced in aged A1+/+ compared with A1-/- mice.Islet arteriolar responses to angiotensin II were stronger in aged A1+/+ mice, this beingassociated with increased NADPH oxidase activity. Aging resulted in multiple changes inA1+/+ compared with A1-/- mice, including enhanced O2- formation in pancreas and VAT,elevated levels of circulating insulin, leptin and pro-inflammatory cytokines (TNF-α, IL-1β,IL-6 & IL-12) and accumulation of CD4+ T-cells in VAT. This was associated with impairedinsulin signaling in VAT from aged A1+/+ mice. Conclusions/interpretations: These studies emphasize that A1 receptors regulate metabolismand islet endocrine and vascular functions during aging by modulating oxidative stress andinflammatory responses.

Available from: 2014-08-28 Created: 2014-08-28 Last updated: 2015-01-22
In thesis
1. Local Purinergic Control of Arteriolar Reactivity in Pancreatic Islets and Renal Glomeruli
Open this publication in new window or tab >>Local Purinergic Control of Arteriolar Reactivity in Pancreatic Islets and Renal Glomeruli
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Local control of regional blood flow is exerted mainly through the arterioles. An adequate minute-to-minute regulation of blood perfusion of the kidney and the pancreas is obtained by the modulation of arteriolar reactivity, which will influence the organ function. The importance of purinergic signaling in this concept has been addressed, with special emphasis on the role of the adenosine A1 receptor. The effects of adenosine on two specialized vascular beds, namely the renal glomerulus and the pancreatic islets, have been examined. Characteristic for these regional circulations is their very high basal blood flow, but with somewhat different responses to vasoconstrictor and vasodilator stimuli. By adapting a unique microperfusion technique it was possible to separately perfuse isolated single mouse arterioles with attached glomeruli or pancreatic islets ex vivo. Microvascular responses were investigated following different additions to the perfusion fluid to directly examine the degree of dilation or constriction of the arterioles. This has been performed on transgenic animals in this thesis, e.g. A1 receptor knockout mice. Also effects of P2Y receptors on islet arterioles were examined in both normoglycemic and type 2 diabetic rats. Furthermore, interference with adenosine transport in glomerular arterioles were examined.. Our studies demonstrate important, yet complex, effects of adenosine and nucleotide signaling on renal and islet microvascular function, which in turn may influence both cardiovascular and metabolic regulations. They highlight the need for further studies of other purinergic receptors in this context, studies that are at currently being investigated.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1024
Keyword
afferent arteriole, islet arteriole, adenosine, A1 receptor, ATP, P2Y receptor, microperfusion, angiotensin II, type 2 diabetes, hypertension, oxidative stress, nitric oxide, tubuloglomerular feedback
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-230770 (URN)978-91-554-9018-8 (ISBN)
Public defence
2014-10-16, C2: 301, BMC, Husargatan 3, Uppsala, 13:00 (English)
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Supervisors
Available from: 2014-09-24 Created: 2014-08-28 Last updated: 2015-01-22

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Gao, XiangSandberg, MonicaPersson, ErikJansson, Leif

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