Daniela Liskiewicz, Aaron Novikoff, Ahmed Khalil, Seun Akindehin, Jonathan E. Campbell, Pietra Candela, Russell L. Castelino, Callum Coupland, Maxime Culot, W. Scott Dodson, Jonathan D. Douros, Hannes Embring, Annette Feuchtinger, Brian Finan, Cristina Garcia-Caceres, Xiao-Bing Gao, Fabien Gosselet, Gerald Grandl, Robert M. Gutgesell, Daniel T. Haas, Martin Jastroch, Ezgi Karaoglu, Pamela Kakimoto, Anna Cristina Kaltenbach, Michaela Keuper, Christine M. Kusminski, Danielle C. Leander, Arkadiusz Liskiewicz, Xue Liu, Gandhari Maity-Kumar, Sara Martinez Martinez, Stephanie A. Mowery, Ruben Nogueiras, Marshall Paisley, Diego Perez-Tilve, Patricia S. S. Petersen, Paul T. Pfluger, Sneha Prakash, Sabine Steffens, Alberto Cebrian-Serrano, Monica Tost, Jordan Wean, Christian Weber, Junichi Yoshida, Zachary Gerhart-Hines, Tamas L. Horvath, Philipp E. Scherer, Randy J. Seeley, Richard D. DiMarchi, Matthias H. Tschöp, Natalie Krahmer, Patrick J. Knerr & Timo D. Müller
GLP-1R–GIPR–PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice
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.
