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.

人口老龄化与肥胖大流行相结合，导致非传染性疾病惊人地增加。在这里，我们发现神秘的腺苷 A2B 受体 (A2B) 在骨骼肌 (SKM) 和棕色脂肪组织 (BAT) 中大量表达，并且可能针对对抗与年龄相关的肌肉萎缩 (肌肉减少症) 和肥胖症。具有 SKM 特异性 A2B 缺失的小鼠表现出肌肉减少、肌肉力量减弱和能量消耗 (EE) 降低，而药理学 A2B 激活抵消了这些过程。A2B 的脂肪组织特异性消融加剧了与年龄相关的过程并降低了 BAT EE，而 A2B 刺激改善了肥胖。在人类中，A2B 表达与 SKM 中的 EE、BAT 活性和白色脂肪中产热脂肪细胞的丰度相关。而且，A2B 激动剂治疗增加了人类脂肪细胞、肌细胞和肌肉外植体的 EE。从机制上讲，A2B 形成腺苷信号传导所需的异二聚体。总体而言，腺苷/A2B 信号将肌肉和 BAT 联系起来，并具有抗衰老和抗肥胖的潜力。