PLoS ONE：A2b型腺苷受体在调节肥胖和II型糖尿病中发挥着重要作用

来自美国波士顿大学医学院的一项研究证实A2b型腺苷受体(A2b-type adenosine receptor, A2bAR)在调节高脂肪和高胆固醇饮食诱导的II型糖尿病症状中发挥着非常重要的作用，而且还鉴定出A2bAR能够作为治疗II型糖尿病的潜在靶标。相关研究发现于2012年7月25日在线发表在PLoS ONE期刊上。

含有高脂肪和高胆固醇的饮食导致身体在调节血糖水平上发生变化。锻炼导致细胞增加腺苷产生。A2bAR是一种自然发生的蛋白受体，存在于细胞膜上，能够被腺苷激活。已知这种受体在调节与II型糖尿病和肥胖相关联的炎症中发挥着重要作用。

为了研究A2bAR激活与含有高脂肪和高胆固醇的饮食之间的关联，研究人员利用一种缺乏A2bAR的实验模式动物开展研究，并将研究结果与对照组进行比较。当给实验模式动物组喂食含有高脂肪和高胆固醇的食物时，有更多的动物患上肥胖和产生II型糖尿病症状。这项研究证实II型糖尿病症状包括血糖水平提高和胰岛素水平增加。然而，当给对照组喂食同样食物时，A2bAR水平增加，导致胰岛素水平、血糖水平和患有肥胖症的动物数量下降。

研究人员也鉴定出A2bAR表达与胰岛素受体底物2(insulin receptor substrate 2, IRS-2)和胰岛素信号存在新的关联。研究结果显示IRS-2水平在缺乏A2bAR的实验模式动物组织中下降，从而导致更高浓度的血糖，其中已知蛋白IRS-2能够调节胰岛素的影响。当利用一种药物试剂来激活喂食富含高脂肪和高胆固醇的食物的对照组体内的A2bAR时，IRS-2水平被上调，能够降低血糖水平。

为了在人身上关联这些研究结果，研究人员接着研究了来自肥胖者的脂肪组织样品。研究结果显示相对于瘦人，A2bAR在来自肥胖者的脂肪组织中高表达，而且与 IRS-2表达强烈地相关联。这些研究结果提示着A2bAR 在维持IRS-2水平上发挥着重要水平，其中IRS-2是血糖和胰岛素体内平衡的一种调节物。

本文编译自Study identifies receptor's role in regulating obesity, type 2 diabetes

doi: 10.1371/journal.pone.0040584
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The A2b Adenosine Receptor Modulates Glucose Homeostasis and Obesity

Hillary Johnston-Cox1,3#, Milka Koupenova1,2,3#, Dan Yang1, Barbara Corkey1,4, Noyan Gokce3,4, Melissa G. Farb3,4, Nathan LeBrasseur1, Katya Ravid

Background High fat diet and its induced changes in glucose homeostasis, inflammation and obesity continue to be an epidemic in developed countries. The A2b adenosine receptor (A2bAR) is known to regulate inflammation. We used a diet-induced obesity murine knockout model to investigate the role of this receptor in mediating metabolic homeostasis, and correlated our findings in obese patient samples. Methodology/Principal Findings Administration of high fat, high cholesterol diet (HFD) for sixteen weeks vastly upregulated the expression of the A2bAR in control mice, while A2bAR knockout (KO) mice under this diet developed greater obesity and hallmarks of type 2 diabetes (T2D), assessed by delayed glucose clearance and augmented insulin levels compared to matching control mice. We identified a novel link between the expression of A2bAR, insulin receptor substrate 2 (IRS-2), and insulin signaling, determined by Western blotting for IRS-2 and tissue Akt phosphorylation. The latter is impaired in tissues of A2bAR KO mice, along with a greater inflammatory state. Additional mechanisms involved include A2bAR regulation of SREBP-1 expression, a repressor of IRS-2. Importantly, pharmacological activation of the A2bAR by injection of the A2bAR ligand BAY 60-6583 for four weeks post HFD restores IRS-2 levels, and ameliorates T2D. Finally, in obese human subjects A2bAR expression correlates strongly with IRS-2 expression. Conclusions/Significance Our study identified the A2bAR as a significant regulator of HFD-induced hallmarks of T2D, thereby pointing to its therapeutic potential.s.