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Liskiewicz, D. ; Novikoff, A. ; Khalil, A. ; Akindehin, S.E. ; Campbell, J.E.* ; Candela, P.* ; Castelino, R.L. ; Coupland, C. ; Culot, M.* ; Dodson, W.S.* ; Douros, J.D.* ; Embring, H.* ; Feuchtinger, A. ; Finan, B.* ; García-Cáceres, C. ; Gao, X.* ; Gosselet, F.* ; Grandl, G. ; Gutgesell, R.M. ; Haas, D. ; Jastroch, M.* ; Karaoglu, Ö.E. ; Kakimoto, P. ; Kaltenbach, A.C.* ; Keuper, M.* ; Kusminski, C.M.* ; Leander, D.C.* ; Liskiewicz, A. ; Liu, X. ; Maity-Kumar, G. ; Martinez, S.M.* ; Mowery, S.A.* ; Nogueiras, R.* ; Paisley, M.* ; Perez-Tilve, D.* ; Petersen, P.S.S.* ; Pfluger, P.T. ; Prakash, S. ; Steffens, S. ; Cebrian Serrano, A. ; Tost, M. ; Wean, J.* ; Weber, C.* ; Yoshida, J.* ; Gerhart-Hines, Z.* ; Horvath, T.L.* ; Scherer, P.E.* ; Seeley, R.J.* ; DiMarchi, R.D.* ; Tschöp, M.H. ; Krahmer, N. ; Knerr, P.J.* ; Müller, T.D.

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

Nature, DOI: 10.1038/s41586-026-10427-5 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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 PPAR alpha, PPAR gamma and PPAR delta-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 PPAR delta 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Activated-receptor-delta; Ppar-alpha; Adipose-tissue; Food-intake; Gamma; Expression; Metabolism; Inflammation; Mechanism; Glucagon
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
CF Pathology & Tissue Analytics (CF-PTA)
Institute of Computational Biology (ICB)
Institute of Diabetes and Cancer (IDC)
Grants Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)