Type 2 diabetes (T2D) is often linked to metabolic syndrome, which assembles various risk factors related to obesity. Plasma levels of adiponectin are decreased in T2D and obese subjects. Aiming to develop a peptide able to bind adiponectin receptors and modulate their signalling pathways, a 12-amino acid sequence homologous in AdipoR1/R2 has been targeted by phage display with a linear 12-mer peptide library. The selected peptide P17 recognises AdipoR1/R2 expressed by skeletal muscle, liver and pancreatic islets. In HepaRG and C2C12 cells, P17 induced the activation of AMPK (AMPKα-pT172) and the expression of succinate dehydrogenase and glucokinase; no cytotoxic effects were observed on HepaRG cells. In db/db mice, P17 promoted body weight and glycaemia stabilisation, decreased plasma triglycerides to the range of healthy mice and increased adiponectin (in high fat-fed mice) and insulin (in chow-fed mice) levels. It restored to the range of healthy mice the tissue levels and subcellular distribution of AdipoR1/R2, AMPKα-pT172 and PPARα-pS12. In liver, P17 reduced steatosis and apoptosis. The docking of P17 to AdipoR is reminiscent of the binding mechanism of adiponectin. To conclude, we have developed an AdipoR1/AdipoR2-targeted peptide that modulates adiponectin signalling pathways and has therapeutic relevance for T2D and obesity associated pathologies.

2 型糖尿病 (T2D) 通常与代谢综合征有关，代谢综合征汇集了与肥胖相关的各种风险因素。T2D 和肥胖受试者的血浆脂联素水平降低。为了开发一种能够结合脂联素受体并调节其信号通路的肽，在 AdipoR1/R2 中同源的 12 个氨基酸序列已被噬菌体展示与线性 12 聚体肽库靶向。选定的肽 P17 识别骨骼肌、肝脏和胰岛表达的 AdipoR1/R2。在HepaRG和C2C12细胞中，P17诱导AMPK（AMPKα-pT172）的活化以及琥珀酸脱氢酶和葡萄糖激酶的表达；未观察到对 HepaRG 细胞的细胞毒性作用。在 db/db 小鼠中，P17 促进体重和血糖稳定，将血浆甘油三酯降低到健康小鼠的范围，并增加脂联素（在高脂肪喂养的小鼠中）和胰岛素（在饲料喂养的小鼠中）水平。它将 AdipoR1/R2、AMPKα-pT172 和 PPARα-pS12 的组织水平和亚细胞分布恢复到健康小鼠的范围内。在肝脏中，P17 减少脂肪变性和细胞凋亡。P17 与 AdipoR 的对接让人想起脂联素的结合机制。总之，我们开发了一种 AdipoR1/AdipoR2 靶向肽，可调节脂联素信号通路，并与 T2D 和肥胖相关病理具有治疗相关性。P17 与 AdipoR 的对接让人想起脂联素的结合机制。总之，我们开发了一种 AdipoR1/AdipoR2 靶向肽，可调节脂联素信号通路，并与 T2D 和肥胖相关病理具有治疗相关性。P17 与 AdipoR 的对接让人想起脂联素的结合机制。总之，我们开发了一种 AdipoR1/AdipoR2 靶向肽，可调节脂联素信号通路，并与 T2D 和肥胖相关病理具有治疗相关性。