GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice
Résumé
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).
Mots clés
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
Domaines
Neurosciences [q-bio.NC]Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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