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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 PMC
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
Korrespondenzautor
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
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Institute of Diabetes and Regeneration Research (IDR)
Research Unit Analytical Pathology (AAP)
Institute of Diabetes and Cancer (IDC)
Förderungen Deutsche Forschungsgemeinschaft (German Research Foundation)