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

Thorsten Gnad; Saskia Scheibler; Ivar von Kügelgen; Camilla Scheele; Ana Kilić; Anja Glöde; Linda S Hoffmann; Laia Reverte-Salisa; Philipp Horn; Samet Mutlu; Ali El-Tayeb; Mathias Kranz; Winnie Deuther-Conrad; Peter Brust; Martin E Lidell; Matthias J Betz; Sven Enerbäck; Jürgen Schrader; Gennady G Yegutkin; Christa E Müller; Alexander Pfeifer

doi:10.1038/nature13816

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

Thorsten Gnad, Saskia Scheibler, Ivar von Kügelgen, Camilla Scheele, Ana Kilić, Anja Glöde, Linda S Hoffmann, Laia Reverte-Salisa, Philipp Horn, Samet Mutlu, Ali El-Tayeb, Mathias Kranz, Winnie Deuther-Conrad, Peter Brust, Martin E Lidell, Matthias J Betz, Sven Enerbäck, Jürgen Schrader, Gennady G Yegutkin, Christa E MüllerAlexander Pfeifer

204 Citationer (Scopus)

Abstract

Brownadipose tissue (BAT)is specialized in energy expenditure,making it a potential target for anti-obesity therapies^1-5. Following exposure to cold,BATis activated by the sympathetic nervous systemwith concomitant release of catecholamines and activation of β-adrenergic receptors^1-5.BecauseBATtherapiesbasedoncold exposureor β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmissionmight be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine inBATfromhamster or rat^6-8. However, the role of adenosine in human BATis unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations.Adenosine is releasedinBATduring stimulation of sympathetic nerves as well as frombrown adipocytes. The adenosineA_2A receptor is themost abundant adenosine receptor inhumanandmurine BAT.Pharmacological blockade or genetic loss ofA_2A receptors inmice causes adecrease inBAT-dependent thermogenesis, whereas treatment with A_2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A_2A receptors or injection of lentiviral vectors expressing theA _2A receptor into white fat induces brown-like cells-so-called beige adipocytes.Importantly, mice fed a high-fat diet and treated with an A _2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A _2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.

Originalsprog	Engelsk
Tidsskrift	Nature
Vol/bind	516
Udgave nummer	7531
Sider (fra-til)	395-9
Antal sider	5
ISSN	0028-0836
DOI	https://doi.org/10.1038/nature13816
Status	Udgivet - 18 dec. 2014

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Gnad, T., Scheibler, S., von Kügelgen, I., Scheele, C., Kilić, A., Glöde, A., Hoffmann, L. S., Reverte-Salisa, L., Horn, P., Mutlu, S., El-Tayeb, A., Kranz, M., Deuther-Conrad, W., Brust, P., Lidell, M. E., Betz, M. J., Enerbäck, S., Schrader, J., Yegutkin, G. G., ... Pfeifer, A. (2014). Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature, 516(7531), 395-9. https://doi.org/10.1038/nature13816

Gnad, T, Scheibler, S, von Kügelgen, I, Scheele, C, Kilić, A, Glöde, A, Hoffmann, LS, Reverte-Salisa, L, Horn, P, Mutlu, S, El-Tayeb, A, Kranz, M, Deuther-Conrad, W, Brust, P, Lidell, ME, Betz, MJ, Enerbäck, S, Schrader, J, Yegutkin, GG, Müller, CE & Pfeifer, A 2014, 'Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors', Nature, bind 516, nr. 7531, s. 395-9. https://doi.org/10.1038/nature13816

@article{e4a1ff181ae0403298203ef8449bcf8b,

title = "Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors",

abstract = "Brownadipose tissue (BAT)is specialized in energy expenditure,making it a potential target for anti-obesity therapies1-5. Following exposure to cold,BATis activated by the sympathetic nervous systemwith concomitant release of catecholamines and activation of β-adrenergic receptors1-5.BecauseBATtherapiesbasedoncold exposureor β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmissionmight be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine inBATfromhamster or rat6-8. However, the role of adenosine in human BATis unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations.Adenosine is releasedinBATduring stimulation of sympathetic nerves as well as frombrown adipocytes. The adenosineA2A receptor is themost abundant adenosine receptor inhumanandmurine BAT.Pharmacological blockade or genetic loss ofA2A receptors inmice causes adecrease inBAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing theA 2A receptor into white fat induces brown-like cells-so-called beige adipocytes.Importantly, mice fed a high-fat diet and treated with an A 2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A 2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.",

keywords = "Adenosine, Adenosine A2 Receptor Agonists, Adipocytes, Adipose Tissue, Brown, Animals, Cells, Cultured, Cricetinae, Diet, Humans, Male, Mesocricetus, Mice, Mice, Inbred C57BL, Phenethylamines, Receptor, Adenosine A2A, Journal Article, Research Support, Non-U.S. Gov't",

author = "Thorsten Gnad and Saskia Scheibler and {von K{\"u}gelgen}, Ivar and Camilla Scheele and Ana Kili{\'c} and Anja Gl{\"o}de and Hoffmann, {Linda S} and Laia Reverte-Salisa and Philipp Horn and Samet Mutlu and Ali El-Tayeb and Mathias Kranz and Winnie Deuther-Conrad and Peter Brust and Lidell, {Martin E} and Betz, {Matthias J} and Sven Enerb{\"a}ck and J{\"u}rgen Schrader and Yegutkin, {Gennady G} and M{\"u}ller, {Christa E} and Alexander Pfeifer",

year = "2014",

month = dec,

day = "18",

doi = "10.1038/nature13816",

language = "English",

volume = "516",

pages = "395--9",

journal = "Nature",

issn = "0028-0836",

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number = "7531",

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TY - JOUR

T1 - Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors

AU - Gnad, Thorsten

AU - Scheibler, Saskia

AU - von Kügelgen, Ivar

AU - Scheele, Camilla

AU - Kilić, Ana

AU - Glöde, Anja

AU - Hoffmann, Linda S

AU - Reverte-Salisa, Laia

AU - Horn, Philipp

AU - Mutlu, Samet

AU - El-Tayeb, Ali

AU - Kranz, Mathias

AU - Deuther-Conrad, Winnie

AU - Brust, Peter

AU - Lidell, Martin E

AU - Betz, Matthias J

AU - Enerbäck, Sven

AU - Schrader, Jürgen

AU - Yegutkin, Gennady G

AU - Müller, Christa E

AU - Pfeifer, Alexander

PY - 2014/12/18

Y1 - 2014/12/18

N2 - Brownadipose tissue (BAT)is specialized in energy expenditure,making it a potential target for anti-obesity therapies1-5. Following exposure to cold,BATis activated by the sympathetic nervous systemwith concomitant release of catecholamines and activation of β-adrenergic receptors1-5.BecauseBATtherapiesbasedoncold exposureor β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmissionmight be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine inBATfromhamster or rat6-8. However, the role of adenosine in human BATis unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations.Adenosine is releasedinBATduring stimulation of sympathetic nerves as well as frombrown adipocytes. The adenosineA2A receptor is themost abundant adenosine receptor inhumanandmurine BAT.Pharmacological blockade or genetic loss ofA2A receptors inmice causes adecrease inBAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing theA 2A receptor into white fat induces brown-like cells-so-called beige adipocytes.Importantly, mice fed a high-fat diet and treated with an A 2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A 2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.

AB - Brownadipose tissue (BAT)is specialized in energy expenditure,making it a potential target for anti-obesity therapies1-5. Following exposure to cold,BATis activated by the sympathetic nervous systemwith concomitant release of catecholamines and activation of β-adrenergic receptors1-5.BecauseBATtherapiesbasedoncold exposureor β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmissionmight be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine inBATfromhamster or rat6-8. However, the role of adenosine in human BATis unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations.Adenosine is releasedinBATduring stimulation of sympathetic nerves as well as frombrown adipocytes. The adenosineA2A receptor is themost abundant adenosine receptor inhumanandmurine BAT.Pharmacological blockade or genetic loss ofA2A receptors inmice causes adecrease inBAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing theA 2A receptor into white fat induces brown-like cells-so-called beige adipocytes.Importantly, mice fed a high-fat diet and treated with an A 2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A 2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.

KW - Adenosine

KW - Adenosine A2 Receptor Agonists

KW - Adipocytes

KW - Adipose Tissue, Brown

KW - Animals

KW - Cells, Cultured

KW - Cricetinae

KW - Diet

KW - Humans

KW - Male

KW - Mesocricetus

KW - Mice

KW - Mice, Inbred C57BL

KW - Phenethylamines

KW - Receptor, Adenosine A2A

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/nature13816

DO - 10.1038/nature13816

M3 - Journal article

C2 - 25317558

SN - 0028-0836

VL - 516

SP - 395

EP - 399

JO - Nature

JF - Nature

IS - 7531

ER -

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

Abstract

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