2. Academic Validation
  3. GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice

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

  • Nat Metab. 2022 Aug;4(8):1071-1083. doi: 10.1038/s42255-022-00617-6.
Carmelo Quarta # 1 2 3,  Kerstin Stemmer # 1 2 4,  Aaron Novikoff # 1 2 5,  Bin Yang 6,  Felix Klingelhuber 1 2,  Alex Harger 1 2,  Mostafa Bakhti 2 7,  Aimee Bastidas-Ponce 2 7,  Eric Baugé 8,  Jonathan E Campbell 9,  Megan Capozzi 9,  Christoffer Clemmensen 10,  Gustav Collden 1 2,  Perla Cota 2 7,  Jon Douros 6,  Daniel J Drucker 11,  Barent DuBois 6,  Annette Feuchtinger 12,  Cristina Garcia-Caceres 1 2,  Gerald Grandl 1 2,  Nathalie Hennuyer 8,  Stephan Herzig 2 13,  Susanna M Hofmann 2 7 14,  Patrick J Knerr 6,  Konxhe Kulaj 1 2,  Fanny Lalloyer 8,  Heiko Lickert 2 7,  Arek Liskiewicz 1 2,  Daniela Liskiewicz 1 2,  Gandhari Maity 1 2,  Diego Perez-Tilve 15,  Sneha Prakash 1 2,  Miguel A Sanchez-Garrido 16,  Qian Zhang 1 2,  Bart Staels 8,  Natalie Krahmer 1 2,  Richard D DiMarchi 17,  Matthias H Tschöp 2 5 18,  Brian Finan 19,  Timo D Müller 20 21
Affiliations

Affiliations

  • 1 Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany.
  • 2 German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • 3 University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France.
  • 4 Molecular Cell Biology, Institute for Theoretical Medicine, University of Augsburg, Augsburg, Germany.
  • 5 Division of Metabolic Diseases, Department of Medicine, Technical University of München, Munich, Germany.
  • 6 Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
  • 7 Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany.
  • 8 Inserm, CHU Lille, Institute of Pasteur de Lille, European Genomic Institute for Genomics, University of Lille, Lille, France.
  • 9 Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA.
  • 10 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 11 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
  • 12 Research Unit Analytical Pathology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
  • 13 Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany.
  • 14 Medical Clinic and Polyclinic IV, Ludwig-Maximilians University of München, Munich, Germany.
  • 15 Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 16 Department of Cell Biology, Physiology and Immunology, Faculty of Medicine, University of Córdoba, Córdoba, Spain.
  • 17 Department of Chemistry, Indiana University, Bloomington, IN, USA.
  • 18 Helmholtz Zentrum München, Neuherberg, Germany.
  • 19 Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA. BFIN@novonordisk.com.
  • 20 Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany. timo.mueller@helmholtz-muenchen.de.
  • 21 German Center for Diabetes Research (DZD), Neuherberg, Germany. timo.mueller@helmholtz-muenchen.de.
  • # Contributed equally.
PMID: 35995995 DOI: 10.1038/s42255-022-00617-6
Abstract

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.

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