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.

doi:10.1038/s42255-022-00617-6

QUARTA, Carmelo
Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale [U1215 Inserm - UB]

STEMMER, Kerstin

NOVIKOFF, Aaron

Langue

Article de revue

Ce document a été publié dans

Nature Metabolism. 2022-08-04, vol. 4, n° 8, p. 1071-1083

Résumé en anglais

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).< Réduire

Mots clés en anglais

Alkanesulfonic Acid

Glucagon Like Peptide 1

Glucagon Like Peptide 1 Receptor

Glucose

Peroxisome Proliferator Activated Receptor Alpha

Phenylpropionic Acid Derivative

Tesaglitazar

Body Weight

Male

Metabolism

Mouse

Non Insulin Dependent Diabetes Mellitus

Obesity

Alkanesulfonates

Diabetes Mellitus

Type 2

Mice

Phenylpropionates

Ppar Alpha

URI

https://oskar-bordeaux.fr/handle/20.500.12278/171831

DOI

http://dx.doi.org/10.1038/s42255-022-00617-6

Project ANR

Rôle de Tbx3 dans la détermination de l'identité fonctionnelle des neurones POMC dans l'obésité - ANR-20-CE14-0046
EGID Diabetes Pole - ANR-10-LABX-0046

Unités de recherche

Neurocentre Magendie - U1215

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