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Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity.

ABSTRACT: The combination of aging populations with the obesity pandemic results in an alarming rise in non-communicable diseases. Here, we show that the enigmatic adenosine A2B receptor (A2B) is abundantly expressed in skeletal muscle (SKM) as well as brown adipose tissue (BAT) and might be targeted to counteract age-related muscle atrophy (sarcopenia) as well as obesity. Mice with SKM-specific deletion of A2B exhibited sarcopenia, diminished muscle strength, and reduced energy expenditure (EE), whereas pharmacological A2B activation counteracted these processes. Adipose tissue-specific ablation of A2B exacerbated age-related processes and reduced BAT EE, whereas A2B stimulation ameliorated obesity. In humans, A2B expression correlated with EE in SKM, BAT activity, and abundance of thermogenic adipocytes in white fat. Moreover, A2B agonist treatment increased EE from human adipocytes, myocytes, and muscle explants. Mechanistically, A2B forms heterodimers required for adenosine signaling. Overall, adenosine/A2B signaling links muscle and BAT and has both anti-aging and anti-obesity potential.

SUBMITTER: Gnad T

PROVIDER: S-EPMC7437516 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity.

Gnad Thorsten T Navarro Gemma G Lahesmaa Minna M Reverte-Salisa Laia L Copperi Francesca F Cordomi Arnau A Naumann Jennifer J Hochhäuser Aileen A Haufs-Brusberg Saskia S Wenzel Daniela D Suhr Frank F Jespersen Naja Zenius NZ Scheele Camilla C Tsvilovskyy Volodymyr V Brinkmann Christian C Rittweger Joern J Dani Christian C Kranz Mathias M Deuther-Conrad Winnie W Eltzschig Holger K HK Niemi Tarja T Taittonen Markku M Brust Peter P Nuutila Pirjo P Pardo Leonardo L Fleischmann Bernd K BK Blüher Matthias M Franco Rafael R Bloch Wilhelm W Virtanen Kirsi A KA Pfeifer Alexander A

Cell metabolism 20200625 1

The combination of aging populations with the obesity pandemic results in an alarming rise in non-communicable diseases. Here, we show that the enigmatic adenosine A2B receptor (A2B) is abundantly expressed in skeletal muscle (SKM) as well as brown adipose tissue (BAT) and might be targeted to counteract age-related muscle atrophy (sarcopenia) as well as obesity. Mice with SKM-specific deletion of A2B exhibited sarcopenia, diminished muscle strength, and reduced energy expenditure (EE), whereas ...[more]

PMID: 32589947

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Project description:RationaleHypertension is the most prevalent life-threatening disease worldwide and is frequently associated with chronic kidney disease (CKD). However, the molecular basis underlying hypertensive CKD is not fully understood.ObjectiveWe sought to identify specific factors and signaling pathways that contribute to hypertensive CKD and thereby exacerbate disease progression.Methods and resultsUsing high-throughput quantitative reverse-transcription polymerase chain reaction profiling, we discovered that the expression level of 5'-ectonucleotidase (CD73), a key enzyme that produces extracellular adenosine, was significantly increased in the kidneys of angiotensin II-infused mice, an animal model of hypertensive nephropathy. Genetic and pharmacological studies in mice revealed that elevated CD73-mediated excess renal adenosine preferentially induced A2B adenosine receptor (ADORA2B) production and that enhanced kidney ADORA2B signaling contributes to angiotensin II-induced hypertension. Similarly, in humans, we found that CD73 and ADORA2B levels were significantly elevated in the kidneys of CKD patients compared with normal individuals and were further elevated in hypertensive CKD patients. These findings led us to further discover that elevated renal CD73 contributes to excess adenosine signaling via ADORA2B activation that directly stimulates endothelin-1 production in a hypoxia-inducible factor-α-dependent manner and underlies the pathogenesis of the disease. Finally, we revealed that hypoxia-inducible factor-α is an important factor responsible for angiotensin II-induced CD73 and ADORA2B expression at the transcriptional level.ConclusionsOverall, our studies reveal that angiotensin II-induced renal CD73 promotes the production of renal adenosine that is a prominent driver of hypertensive CKD by enhanced ADORA2B signaling-mediated endothelin-1 induction in a hypoxia-inducible factor-α-dependent manner. The inhibition of excess adenosine-mediated ADORA2B signaling represents a novel therapeutic target for the disease.

Dataset Information

Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity.

Publications

Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity.

Similar Datasets

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