Abrogation of adenosine A₁ receptor signalling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses

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.