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

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Quarta, Carmelo | Stemmer, Kerstin | Novikoff, Aaron | Yang, Bin | Klingelhuber, Felix | Harger, Alex | Bakhti, Mostafa | Bastidas-Ponce, Aimee | Bauge, Eric | Campbell, Jonathan E. | Capozzi, Megan | Clemmensen, Christoffer | Collden, Gustav | Cota, Perla | Douros, Jon | Drucker, Daniel J. | Dubois, Barent | Feuchtinger, Annette | Garcia-Caceres, Cristina | Grandl, Gerald | Hennuyer, Nathalie | Herzig, Stephan | Hofmann, Susanna M. | Knerr, Patrick J. | Kulaj, Konxhe | Lalloyer, Fanny | Lickert, Heiko | Liskiewicz, Arek | Liskiewicz, Daniela | Maity, Gandhari | Perez-Tilve, Diego | Prakash, Sneha | Sanchez-Garrido, Miguel A. | Zhang, Qian | Staels, Bart | Krahmer, Nathalie | Dimarchi, Richard D. | Tschop, Matthias H. | Finan, Brian | Muller, Timo D.

Edité par CCSD ; Nature Publishing Group -

International audience. 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. © 2022, The Author(s).

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