Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors


Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors

Gnad, T.; Scheibler, S.; von Kügelgen, I.; Scheele, C.; Kilic, A.; Glöde, A.; Hoffmann, L.; Reverte, L.; Horn, P.; Mutlu, S.; El-Tayeb, A.; Kranz, M.; Deuther-Conrad, W.; Brust, P.; Lidell, M.; Betz, M.; Enerbäck, S.; Schrader, J.; Yegutkin, G.; Mueller, C.; Pfeifer, A.

Brown adipose tissue (BAT) is specialised in energy expenditure making it a potential target for anti-obesity therapies. Following cold-exposure, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of β-adrenergic receptors. Because BAT therapies based on cold-exposure or β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat. However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A2A receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A2A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A2A receptor into white fat induces brown-like cells - so called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A2A agonist are leaner with improved glucose tolerance. Taken together, we demonstrate that adenosine/A2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity - findings that reveal new possibilities for developing novel obesity therapies.

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Publ.-Id: 20769