GLP-1R–GIPR–PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice
Abstract
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 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.
Article Details
Authors (53)
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