Quarta, Carmelo; Stemmer, Kerstin; Novikoff, Aaron; Yang, Bin; Klingelhuber, Felix; Harger, Alex; Bakhti, Mostafa; Bastidas-Ponce, Aimee; Baugé, 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, Natalie; DiMarchi, Richard D; Tschöp, Matthias H; Finan, Brian; Müller, Timo D     «

Quarta, Carmelo; Stemmer, Kerstin; Novikoff, Aaron; Yang, Bin; Klingelhuber, Felix; Harger, Alex; Bakhti, Mostafa; Bastidas-Ponce, Aimee; Baugé, 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; Lis...     »

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.      «

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/...     »