Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor-dependent manner
Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor-dependent manner
复制标题
针对血管紧张素 II 受体的免疫疗法以瘦素受体依赖性方式改善胰岛素抵抗
DOI：
10.1096/fj.202000300r
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Cheng X.
中科院分区：
文献类型：
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作者：
Zheng J.;Ding J.;Liao M.;Qiu Z.;Yuan Q.;Mai W.;Dai Y.;Zhang H.;Wu H.;Wang Y.;Liao Y.;Chen X.;Cheng X.
据报道，血管紧张素 II 1 型受体 (AT1R) 信号通路可调节葡萄糖代谢。针对AT1R，我们课题组发明了ATRQβ-001疫苗，这是一种阻断AT1R激活的新型免疫治疗策略。在这里，我们评估了 ATRQβ-001 疫苗对胰岛素抵抗的治疗效果，并研究了其机制。我们的结果表明，ATRQβ-001 疫苗和针对表位 ATR-001 的特异性单克隆抗体 (McAb-ATR) 降低了空腹血清胰岛素浓度，并改善了 inob/ob 小鼠的葡萄糖和胰岛素耐受性。这些有益效果在高脂肪饮食诱导的肥胖小鼠中得到了验证。 McAb-ATR 激活骨骼肌和胰岛素抵抗 C2C12 肌管中的胰岛素信号传导，而不影响 ofob/obmice 的肝脏或白色脂肪组织。从机制上讲，在瘦素受体敲低的 indb/db 小鼠和 C2C12 肌管中，McAb-ATR 对胰岛素抵抗的有利影响被消除。 AT1R 敲低也消除了 McAb-ATR 对 C2C12 肌管的影响。此外，McAb-ATR 治疗能够激活骨骼肌 ofob/obmice 和 C2C12 肌管中瘦素受体介导的 JAK2/STAT3 信号传导。此外，血管紧张素 II 下调了 ofob/oband 饮食诱导的肥胖小鼠骨骼肌中的瘦素信号传导。我们证明 ATRQβ-001 疫苗和 McAb-ATR 可以改善全身胰岛素抵抗，并以瘦素受体依赖性方式调节骨骼肌中的葡萄糖代谢。我们的数据表明，针对 AT1R 的免疫疗法是治疗胰岛素抵抗的一种新策略。
The angiotensin II type 1 receptor (AT1R) signaling pathway is reported to modulate glucose metabolism. Targeting AT1R, our group invented ATRQβ‐001 vaccine, a novel immunotherapeutic strategy to block the activation of AT1R. Here, we evaluated the therapeutic efficacy of ATRQβ‐001 vaccine in insulin resistance, and investigated the mechanism. Our results showed that ATRQβ‐001 vaccine and specific monoclonal antibody against epitope ATR‐001 (McAb‐ATR) decreased fasting serum insulin concentration and improved glucose and insulin tolerance inob/obmice. These beneficial effects were verified in high‐fat diet‐induced obese mice. McAb‐ATR activated insulin signaling in skeletal muscle and insulin‐resistant C2C12 myotubes without affecting liver or white adipose tissue ofob/obmice. Mechanistically, the favorable impact of McAb‐ATR on insulin resistance was abolished indb/dbmice and in C2C12 myotubes with leptin receptor knockdown. AT1R knockdown also eradicated the effects of McAb‐ATR in C2C12 myotubes. Furthermore, McAb‐ATR treatment was able to activate the leptin receptor‐mediated JAK2/STAT3 signaling in skeletal muscle ofob/obmice and C2C12 myotubes. Additionally, angiotensin II downregulated the leptin signaling in skeletal muscle ofob/oband diet‐induced obese mice. We demonstrated that ATRQβ‐001 vaccine and McAb‐ATR improved whole‐body insulin resistance and regulated glucose metabolism in skeletal muscle in a leptin receptor‐dependent manner. Our data suggest that immunotherapy targeting AT1R is a novel strategy for treating insulin resistance.