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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 653, 776–785 (2026)
Verlagsversion Forschungsdaten 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Activated-receptor-delta; Ppar-alpha; Adipose-tissue; Food-intake; Gamma; Expression; Metabolism; Inflammation; Mechanism; Glucagon
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Quellenangaben Band: 653, Heft: , Seiten: 776–785 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
CF Pathology & Tissue Analytics (CF-PTA)
Institute of Computational Biology (ICB)
Institute of Diabetes and Cancer (IDC)
Förderungen Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)