德国糖尿病和肥胖研究所Timo D. Müller小组提出了GLP-1R-GIPR-PPARα /γ/δ五效激动剂纠正小鼠肥胖和糖尿病。2026年4月29日，国际知名学术期刊《自然》发表了这一成果。

为了进一步提高GLP-1R-GIPR共激动剂的代谢功效，该团队报道了一种单分子五效激动剂的开发，该激动剂通过靶向递送到表达GLP-1R和GIPR的细胞，将GLP-1R- GIPR共激动剂的减肥和降血糖作用与lanifbranor的胰岛素增敏和抗炎作用结合起来。在体外，GLP-1-GIP-lanifbranor与GLP-1-GIP在肠促胰岛素受体信号传导方面没有区别，并且在离体小鼠胰岛中表现出相同的胰岛素分泌刺激。然而，在体内，GLP-1–GIP-lanifbranor优于GLP-1R-GIPR共激动作用和semaglutide，通过协同肠促胰岛素和PPAR作用，进一步降低肥胖和胰岛素抵抗小鼠的体重、食物摄入量和高血糖。GLP-1–GIP-lanifbranor的代谢作用在GLP-1R、GIPR或PPARδ基因抑制的小鼠中被减弱，而在DIO双肠促胰岛素受体敲除的小鼠中则不存在，这表明GLP-1–GIP-lanifbranor在治疗肥胖和糖尿病方面具有重要的治疗价值。

研究人员表示，有越来越多的有效药物可以改善肥胖相关的代谢功能障碍；GLP-1R-GIPR共激动剂在肥胖和2型糖尿病的治疗中是有效的，而lanifbrana（一种核作用的PPARα、PPARγ和ppar δ的小分子三重激动剂）正在临床3期试验中用于治疗代谢功能障碍相关的脂肪性肝炎。

附：英文原文

Title: GLP-1R–GIPR–PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice

Author: Liskiewicz, Daniela, Novikoff, Aaron, Khalil, Ahmed, Akindehin, Seun, Campbell, Jonathan E., Candela, Pietra, Castelino, Russell L., Coupland, Callum, Culot, Maxime, Dodson, W. Scott, Douros, Jonathan D., Embring, Hannes, Feuchtinger, Annette, Finan, Brian, Garcia-Caceres, Cristina, Gao, Xiao-Bing, Gosselet, Fabien, Grandl, Gerald, Gutgesell, Robert M., Haas, Daniel T., Jastroch, Martin, Karaoglu, Ezgi, Kakimoto, Pamela, Kaltenbach, Anna Cristina, Keuper, Michaela, Kusminski, Christine M., Leander, Danielle C., Liskiewicz, Arkadiusz, Liu, Xue, Maity-Kumar, Gandhari, Martinez, Sara Martinez, Mowery, Stephanie A., Nogueiras, Ruben, Paisley, Marshall, Perez-Tilve, Diego, Petersen, Patricia S. S., Pfluger, Paul T., Prakash, Sneha, Steffens, Sabine, Cebrian-Serrano, Alberto, Tost, Monica, Wean, Jordan, Weber, Christian, Yoshida, Junichi, Gerhart-Hines, Zachary, Horvath, Tamas L., Scherer, Philipp E., Seeley, Randy J., DiMarchi, Richard D., Tschp, Matthias H., Krahmer, Natalie, Knerr, Patrick J., Mller, Timo D.

Issue&Volume: 2026-04-29

Abstract: There are increasing numbers of effective drugs to improve obesity-linked metabolic dysfunction; GLP-1R–GIPR co-agonism is effective in the management of obesity and type 2 diabetes1,2, and lanifibranor—a nuclear-acting small-molecule triple agonist of PPARα, PPARγ and PPARδ—is in clinical phase 3 trials for the treatment of metabolic dysfunction-associated steatohepatitis3. Here, seeking to further improve the metabolic efficacy of GLP-1R–GIPR co-agonism, we report the development of a unimolecular quintuple agonist that combines the body weight-reducing and blood glucose-lowering effects of GLP-1R–GIPR co-agonism with the insulin-sensitizing and anti-inflammatory effects of lanifibranor via its targeted delivery into GLP-1R- and GIPR-expressing cells. In vitro, GLP-1–GIP–lanifibranor is indistinguishable from GLP-1–GIP in relation to incretin receptor signalling and shows equal stimulation of insulin secretion in isolated mouse islets. In vivo, however, GLP-1–GIP–lanifibranor outperforms GLP-1R–GIPR co-agonism and semaglutide, further decreasing body weight, food intake and hyperglycaemia in obese and insulin-resistant mice through synergistic incretin and PPAR action. The metabolic action of GLP-1–GIP–lanifibranor is blunted in mice with genetic or pharmacological inhibition of GLP-1R, GIPR or PPARδ and is absent in DIO double incretin receptor-knockout mice, collectively suggesting that GLP-1–GIP–lanifibranor has substantial therapeutic value in the treatment of obesity and diabetes.

DOI: 10.1038/s41586-026-10427-5

Source: https://www.nature.com/articles/s41586-026-10427-5