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Quarta, C. ; Stemmer, K. ; Novikoff, A. ; Yang, B.* ; Klingelhuber, F. ; Harger, A. ; Bakhti, M. ; Bastidas-Ponce, A. ; Baugé, E.* ; Campbell, J.E.* ; Capozzi, M.E.* ; Clemmensen, C.* ; Collden, G. ; Cota, P. ; Douros, J.* ; Drucker, D.J.* ; Dubois, B.* ; Feuchtinger, A. ; García-Cáceres, C. ; Grandl, G. ; Hennuyer, N.* ; Herzig, S. ; Hofmann, S.M. ; Knerr, P.J.* ; Kulaj, K. ; Lalloyer, F.* ; Lickert, H. ; Liskiewicz, A. ; Liskiewicz, D. ; Maity-Kumar, G. ; Perez-Tilve, D.* ; Prakash, S. ; Sanchez-Garrido, M.A.* ; Zhang, Q. ; Staels, B.* ; Krahmer, N. ; DiMarchi, R.D.* ; Tschöp, M.H. ; Finan, B.* ; Müller, T.D.

GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice.

Nat. Metab. 4, 1071-1083 (2022)
Verlagsversion Forschungsdaten DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography-mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Zeitschrift Nature metabolism
Quellenangaben Band: 4, Heft: 8, Seiten: 1071-1083 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort London
Begutachtungsstatus Peer reviewed
Förderungen Deutsche Forschungsgemeinschaft (German Research Foundation)