GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice PMID: 35995995

Target-related Cytokines

2026-09-23

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

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. [email protected].
20. Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany. [email protected].
21. German Center for Diabetes Research (DZD), Neuherberg, Germany. [email protected].
# Contributed equally.

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.