title: Abrogation of adenosine A1 receptor signalling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses.
abstract: OBJECTIVE
  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 (A1(-/-)) and wild-type (A1(+/+)) 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 A1(+/+) compared with A1(-/-) 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 A1(+/+) compared with A1(-/-) mice. Islet arteriolar responses to angiotensin II were stronger in aged A1(+/+) mice, this being associated with increased NADPH oxidase activity. Ageing resulted in multiple changes in A1(+/+) compared with A1(-/-) 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 A1(+/+) mice.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz Väg 2, SE-171 77, Stockholm, Sweden.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Monica
authors.initials: M
authors.lastname: Sandberg
authors.forename: Christa
authors.initials: C
authors.lastname: Zollbrecht
authors.forename: Xing-Mei
authors.initials: XM
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Hezel
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Maria
authors.initials: M
authors.lastname: Peleli
authors.forename: En-Yin
authors.initials: EY
authors.lastname: Lai
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: A Erik G
authors.initials: AE
authors.lastname: Persson
authors.forename: Bertil B
authors.initials: BB
authors.lastname: Fredholm
authors.forename: Leif
authors.initials: L
authors.lastname: Jansson
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlström
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001823:Body Composition / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics; D007249:Inflammation / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000098:blood supply; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008660:Metabolism / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D043682:Receptor, Adenosine A1 / Q000235:genetics*; D012039:Regional Blood Flow / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016207:Cytokines; D007328:Insulin; D008562:Membrane Glycoproteins; D043682:Receptor, Adenosine A1; D000804:Angiotensin II; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
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