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GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice
- Source :
- Quarta, C, Stemmer, K, Novikoff, A, Yang, B, Klingelhuber, F, Harger, A, Bakhti, M, Bastidas-Ponce, A, Baugé, E, Campbell, J E, Capozzi, M, Clemmensen, C, Collden, G, Cota, P, Douros, J, Drucker, D J, DuBois, B, Feuchtinger, A, Garcia-Caceres, C, Grandl, G, Hennuyer, N, Herzig, S, Hofmann, S M, Knerr, P J, Kulaj, K, Lalloyer, F, Lickert, H, Liskiewicz, A, Liskiewicz, D, Maity, 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 2022, ' GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice ', Nature Metabolism, vol. 4, no. 8, pp. 1071-1083 . https://doi.org/10.1038/s42255-022-00617-6, Nature Metabolism, Nat. Metab. 4, 1071-1083 (2022)
- Publication Year :
- 2021
-
Abstract
- 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.
Details
- ISSN :
- 25225812
- Volume :
- 4
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Nature metabolism
- Accession number :
- edsair.doi.dedup.....7d8cb25c43d6de39a162496e77b8cbe0