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

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

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.

Original languageEnglish
JournalNature Metabolism
Issue number8
Pages (from-to)1071-1083
Number of pages13
Publication statusPublished - 2022

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© 2022, The Author(s).

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