Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues

  1. Jonathan D. Douros
  2. Megan Capozzi
  3. Aaron Novikoff
  4. Jacek Mokrosinski
  5. Barent DuBois
  6. Joseph Stock
  7. Rebecca Rohlfs
  8. Mikayla Anderson
  9. Dominika J. Jedrzejcyk
  10. Svend Poulsen
  11. Erik Oude Blenke
  12. Tomas Dago
  13. Kasper Huus
  14. Peder L. Nørby
  15. Sune Kobberup
  16. Marita Rivir
  17. Joyce Sorrell
  18. Stephanie Mowery
  19. Daniel J. Drucker
  20. David A. D’Alessio
  21. Jonathan E. Campbell
  22. Timo D. Müller
  23. Diego Perez-Tilve
  24. Patrick J. Knerr
  25. Brian Finan
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Abstract

Objective

Unimolecular triagonists drive substantial weight loss in patients with obesity (PwO) by engaging the glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) receptors to reduce food intake (FI) and the hepatic glucagon (Gcg) receptor to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R monoagonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes.

Methods

We used an attenuated adenovirus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure.

Results

Agonism of the ectopic GLP-1R with either semaglutide, a low internalization GLP-1R agonist (Sema584), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to agonist treatment alone.

Conclusions

This represents a novel mechanism for achieving polypharmacy to treat obesity.

Highlights

  • A Glp1r encoding AAV induces expression of a functional receptor mouse livers.

  • Endogenous GLP-1R does not mediate semaglutide clearance.

  • Ectopic GLP-1R mediates semaglutide clearance.

  • Ectopic, hepatic Glp1r plus semaglutide enhances weight loss in mice.

  • Ectopic, hepatic Glp1r plus a dual incretin agonist enhances weight loss in mice.

Article activity feed

  1. Version published to 10.1101/2025.04.01.646483 on bioRxiv