Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies1,2,3,4,5. Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of β-adrenergic receptors1,2,3,4,5. 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 rat6,7,8. 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 A2A receptors in mice causes a decrease in BAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing the A2A 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, our results demonstrate that adenosine–A2A 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.
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Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004)
Kajimura, S. & Saito, M. A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annu. Rev. Physiol. 76, 225–249 (2013)
Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nature Med. 19, 1252–1263 (2013)
Bartelt, A. & Heeren, J. Adipose tissue browning and metabolic health. Nature Rev. Endocrinol. 10, 24–36 (2014)
Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014)
Schimmel, R. J. & McCarthy, L. Role of adenosine as an endogenous regulator of respiration in hamster brown adipocytes. Am. J. Physiol. 246, C301–C307 (1984)
Szillat, D. & Bukowiecki, L. J. Control of brown adipose tissue lipolysis and respiration by adenosine. Am. J. Physiol. 245, E555–E559 (1983)
Woodward, J. A. & Saggerson, E. D. Effect of adenosine deaminase, N6-phenylisopropyladenosine and hypothyroidism on the responsiveness of rat brown adipocytes to noradrenaline. Biochem. J. 238, 395–403 (1986)
Abbracchio, M. P., Burnstock, G., Verkhratsky, A. & Zimmermann, H. Purinergic signalling in the nervous system: an overview. Trends Neurosci. 32, 19–29 (2009)
Gourine, A. V., Wood, J. D. & Burnstock, G. Purinergic signalling in autonomic control. Trends Neurosci. 32, 241–248 (2009)
Zimmermann, H., Zebisch, M. & Strater, N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal. 8, 437–502 (2012)
Fredholm, B. B., IJzerman, A. P., Jacobson, K. A., Linden, J. & Müller, C. E. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors–an update. Pharmacol. Rev. 63, 1–34 (2011)
Johansson, S. M., Lindgren, E., Yang, J. N., Herling, A. W. & Fredholm, B. B. Adenosine A1 receptors regulate lipolysis and lipogenesis in mouse adipose tissue—interactions with insulin. Eur. J. Pharmacol. 597, 92–101 (2008)
McMahon, K. K. & Schimmel, R. J. Apparent absence of alpha-2 adrenergic receptors from hamster brown adipocytes. Life Sci. 30, 1185–1192 (1982)
Unelius, L., Mohell, N. & Nedergaard, J. Cold acclimation induces desensitization to adenosine in brown fat cells without changing receptor binding. Am. J. Physiol. 258, C818–C826 (1990)
Rodriguez, A. M. et al. Transplantation of a multipotent cell population from human adipose tissue induces dystrophin expression in the immunocompetent mdx mouse. J. Exp. Med. 201, 1397–1405 (2005)
Bordicchia, M. et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J. Clin. Invest. 122, 1022–1036 (2012)
Jespersen, N. Z. et al. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab. 17, 798–805 (2013)
Lidell, M. E. et al. Evidence for two types of brown adipose tissue in humans. Nature Med. 19, 631–634 (2013)
Chen, J. F. et al. A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J. Neurosci. 19, 9192–9200 (1999)
Frontini, A. & Cinti, S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 11, 253–256 (2010)
Speakman, J. R. & O'Rahilly, S. Fat: an evolving issue. Dis. Model. Mech. 5, 569–573 (2012)
Chen, Y. et al. miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit. Nature Commun. 4, 1769 (2013)
von Kügelgen, I., Allgaier, C., Schobert, A. & Starke, K. Co-release of noradrenaline and ATP from cultured sympathetic neurons. Neuroscience 61, 199–202 (1994)
Betz, M. J. et al. Presence of brown adipocytes in retroperitoneal fat from patients with benign adrenal tumors: relationship with outdoor temperature. J. Clin. Endocrinol. Metab. 98, 4097–4104 (2013)
Helenius, M., Jalkanen, S. & Yegutkin, G. Enzyme-coupled assays for simultaneous detection of nanomolar ATP, ADP, AMP, adenosine, inosine and pyrophosphate concentrations in extracellular fluids. Biochim. Biophys. Acta 1823, 1967–1975 (2012)
Bonner, F. et al. Ecto-5′-nucleotidase on immune cells protects from adverse cardiac remodeling. Circ. Res. 113, 301–312 (2013)
We thank D. Hass, S. Kipschull, N. Galicki James, B. Steckel, J. Mülich, M. Schneider and G. Petersson for technical assistance. We thank M. Idzko for A2A−/− mice. A.P. was supported by the Deutsche Forschungsgemeinschaft (DFG); S.S. and L.R.-S. were supported by the DFG-funded Research Training Group 1873 “Pharmacology of 7TM-receptors and downstream signalling pathways”; C. S. was supported by the Lundbeck Foundation and Novo Nordisk A/S. CIM is supported by the Danish National Research Foundation (DNRF55) and CFAS is supported by Trygfonden. A.K. and L.S.H. were supported by BONFOR. A.G. was supported by the Bonn International Graduate School DrugS and the Federal Ministry of Education and research. M.E.L. was supported by the Swedish Research Council (2013-4466). S.E. was supported by the Swedish Research Council (2010-3281, 2012-1652), The Knut and Alice Wallenberg Foundation, Sahlgrenska’s University Hospital (LUA-ALF), European Union grants (HEALTH-F2-2011-278373; DIABAT), the Inga Britt and Arne Lundgren Foundation, the Söderberg Foundation, and the King Gustaf V and Queen Victoria Freemason Foundation.
The authors declare no competing financial interests.
Extended data figures and tables
a, b, Relative mRNA expression was analysed in (a) human brown adipocytes (BA) and (b) human white adipocytes (WA) after 8 h treatment with adenosine (BA: 70 nM; WA: 1,200 nM) for 8 h. c, Lipolysis in primary human brown adipocytes treated with adenosine and/or noradrenaline (NE). d, e, Glycerol release in response to increasing concentrations of adenosine in primary murine white adipocytes after (d) knockdown of the adenosine A1 receptor with shRNA or (e) inhibition of A1 receptor with PSB-36 (150 nM) f, Adenosine-induced lipolysis in murine brown adipocytes in the presence or absence of noradrenaline. n = 4; *P < 0.05. Error bars, s.e.m.
a, b, Murine brown adipocytes (a) or white adipocytes (b) were treated with adenosine (BA: 1 nM; WA: 100 nM) or the A2A agonist CGS21680 (150 nM) for 8 h and gene expression of indicated thermogenic markers was analysed. n = 5; *P < 0.05. Error bars, s.e.m.
a, Lipolysis in murine brown adipocytes treated with either adenosine alone or after pre-treatment with A2A (MSX-2) and A2B (PSB-603) receptor antagonists. b, c, cAMP levels (b) and oxygen consumption (c) of murine brown adipocytes treated with either noradrenaline, adenosine or receptor antagonists and agonists. d, Lipolysis of BAT explants treated with noradrenaline, adenosine or A2A agonist (CGS21680). e, Expression of adenosine receptors in mature murine brown adipocytes and white adipocytes compared to respective pre-adipocytes. f, Adenosine receptor expression in BAT of Syrian golden hamster. n = 3 (a–e); n = 8 (f); *P < 0.05. Error bars, s.e.m.
a, Quantification of neck area surface temperatures of newborn WT and A2A−/− littermates. b, Oxygen consumption in control and A2A−/− mice at thermoneutrality (30 °C). c, Body weight of A2A−/− and WT mice. d, e, Locomotor activity of mice analysed at 30 °C (d) or 4 °C (e). f, Representative immunohistochemistry of BAT of WT and A2A−/− littermates stained with either haematoxylin and eosin or antibody against UCP1. g, Representative Oil Red-O staining of differentiated WT or A2A−/− brown adipocytes. h, Representative immunoblots of adipogenic (PPARγ, aP2) and thermogenic marker (UCP1) expression in WT and A2A−/− brown adipocytes. cGMP, 100 µM cGMP. i, Quantification of UCP1, aP2 and PPARγ protein levels. j, Lipolysis after treatment of WT or A2A−/− brown adipocytes with CGS21680. n = 3 (a–e, i, j); *P < 0.05. Error bars, s.e.m.
a, b, Murine brown adipocytes (BA) (a) or white adipocytes (WA) (b) or freshly isolated BAT (c) and iWAT (d) from WT or A2A−/− animals were treated with adenosine (brown adipocytes and BAT: 1 nM; white adipocytes and iWAT: 100 nM) or the A2A agonist CGS21680 (150 nM) and respiration was measured. n = 4; *P < 0.05. Error bars, s.e.m.
a, b, Oxygen consumption (a) and locomotor activity (b) in mice treated with A2A agonist (PSB-0777). c, locomotor activity of mice shown in Fig. 2d, e. d, e, Whole body oxygen consumption in mice treated with noradrenaline or CGS21680 with propranolol pre-treatment. f, PET/MRI imaging of mice that were treated with vehicle, noradrenaline and PSB-0777 before injection of FDG. Arrows indicate interscapular area demonstrating increased uptake of radioactivity by BAT. g, Localization of the area shown in (f). h, i, Expression of A2A in BAT of mice exposed to 4 °C or room temperature (control) (h) and brown adipocytes after incubation with noradrenaline (1 µM) or cAMP (200 µM) (i). j, Locomotor activity of mice shown in Fig. 2g, h. k, Abundance of noradrenaline in mice exposed to 4 °C treated with or without A2A antagonist MSX-3. n = 3 (a–f, h–k); *P < 0.05. Error bars, s.e.m.
a, b, Concentration of ATP (a) and adenosine (b) in BAT isolated from CD73−/− and WT mice subjected to EFS. c, d, Concentration of ATP (c) and adenosine (d) in BAT treated with phenoxybenzamine (10 μM) or vehicle. e, ATP concentrations in supernatant of murine brown adipocytes after treatment with noradrenaline in presence or absence of propranolol. n = 3; *P < 0.05. Error bars, s.e.m.
a, Weight of iWAT and gWAT. b, c, Food intake (b) and locomotor activity (c) of mice on HFD depicted in Fig. 4a–c. d, Locomotor activity of mice shown in Fig. 4d. e, Area under the curve of glucose tolerance. f, g, Thermogenic marker in BAT (f) or iWAT (g). h, Abundance of noradrenaline in BAT and iWAT. i, Alternatively activated macrophage markers in BAT. n = 6; *P < 0.05. Error bars, s.e.m.
a, PGC1α expression in iWAT of mice treated with A2A agonist (CGS21680) or CL316,243 for 10 days. b, Schematic representation of lentiviral constructs. c, d, PGC1α expression (c) in murine white adipocytes infected with either control virus (rrl) or LVA2A treated with adenosine or CGS21680 and lipolysis (d) after treatment with adenosine, CGS21680, MSX-2 (A2A antagonist) or adenosine deaminase (ADA). e–h, Expression of A2A (e), adipocyte diameter (f), proinflammatory cytokines (g) and thermogenic marker genes (h) six weeks after injection of LVGFP or LVA2A into iWAT. n = 4 (a), n = 3 (c–h); *P < 0.05. Error bars, s.e.m.
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Gnad, T., Scheibler, S., von Kügelgen, I. et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516, 395–399 (2014). https://doi.org/10.1038/nature13816
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