GLP-1R–GIPR–PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice
- 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
2026-04-29
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 diabetes 1,2 , 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 steatohepatitis 3 . 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.