Editors' ChoiceMetabolism

Stimulating Fat with Adenosine

Sci. Signal.  23 Dec 2014:
Vol. 7, Issue 357, pp. ec356
DOI: 10.1126/scisignal.aaa5291

Whereas white adipose tissue (WAT) stores energy in the form of lipids, brown adipose tissue (BAT) consumes energy to generate heat. In BAT, lipolysis releases fatty acids that activate the brown fat-specific mitochondrial uncoupling protein UCP1, which causes metabolic energy to be released as heat instead of being used to drive adenosine triphosphatase (ATP) synthesis. Upon exposure to cold, catecholamines released by the sympathetic nervous system activate BAT, and Gnad et al. report that adenosine also stimulates brown fat. In primary and cultured human and mouse brown adipocytes, adenosine stimulated lipolysis, enhanced noradrenaline-induced lipolysis, and increased the expression of thermogenesis markers. The adenosine receptors A2A or A2B were more abundant in brown adipocytes than in white adipocytes, and experiments with receptor agonists and antagonists demonstrated that these receptors mediated the effects of adenosine in brown adipocytes. Newborn A2A-/- mice exhibited reduced thermogenesis compared with wild-type littermates, and adult A2A-/- mice consumed less oxygen than wild-type mice following cold exposure. Experiments in vivo and in primary brown adipocytes using agonists and antagonists of A2A indicated that adenosine signaling through A2A was important for increased thermogenesis, respiration, and lipolysis in BAT in response to cold. Injection of an A2A agonist caused weight loss, a decrease in fat mass, improved glucose tolerance, and increased thermogenesis in mice fed a high-fat diet. Mice treated with an A2A agonist for several days also exhibited signs of "browning" in their WAT, with white adipocytes taking on characteristics typical of brown adipocytes. When fed a high-fat diet, mice expressing A2A in white adipocytes showed increased thermogenesis and lipolysis in WAT and reduced adipocyte hypertrophy and inflammatory cytokine production. Electrical stimulation caused sympathetic neurons in BAT to release noradrenaline and ATP, which is broken down extracellularly to yield adenosine. Stimulating brown adipocytes with noradrenaline caused the cells to release adenosine, indicating that both neurons and brown fat itself could be a source of adenosine in BAT. These results show that adenosine activates brown fat and identify stimulating adenosine signaling as potentially therapeutically useful for treating obesity.

T. Gnad, S. Scheibler, I. von Kügelgen, C. Scheele, A. Kilić, A. Glöde, L. S. Hoffmann, L. Reverte-Salisa, P. Horn, S. Mutlu, A. El-Tayeb, M. Kranz, W. Deuther-Conrad, P. Brust, M. E. Lidell, M. J. Betz, S. Enerbäck, J. Schrader, G. G. Yegutkin, C. E. Müller, A. Pfeifer, Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516, 395–399 (2014). [PubMed]