Journal Article

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

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

2022

Overview

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. A conjugate drug consisting of GLP-1 receptor agonist and the PPARɑ/ɣ dual-agonist tesaglitazar is shown to have superior anti-diabetic effects than monotherapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/109 / 13/51 / 14 / 14/19 / 14/35 / 38 / 45 / 59 / 631/154/436 / 631/443/319/1642/393 / 64 / 64/60 / 692/699/2743/137/773 / 82 / 82/58 / 96 / 96/1 / 96/106 / Acids / Agonists / Biomedical and Life Sciences / Body fat / Body weight / Diabetes mellitus (non-insulin dependent) / Food / Food intake / Glucose / Glucose metabolism / Hyperglycemia / Hypothalamus / Independent study / Insulin resistance / Life Sciences / Ligands / Lipid metabolism / Lipids / Liquid chromatography / Mass spectroscopy / Metabolism / Neurons and Cognition / Obesity / Peroxisome proliferator-activated receptors / Proteomics