2. Academic Validation
  3. A brain reward circuit inhibited by next-generation weight-loss drugs in mice

A brain reward circuit inhibited by next-generation weight-loss drugs in mice

  • Nature. 2026 Jun;654(8120):1055-1064. doi: 10.1038/s41586-026-10444-4.
Elizabeth N Godschall # 1,  Taha Bugra Gungul # 1,  Isabelle R Sajonia # 1,  Aleyna K Buyukaksakal 1,  Orien Li 1,  Sophia Ogilvie 1,  Austin B Keeler 1,  Guilian Tian 2,  Yu Shi 1,  Omar Koita 3 4,  Chloe Xinzhu Guo 1,  Tyler C J Deutsch 5 6,  Eric J Steacy 5 7,  Maisie Crook 1,  YuChen Zhang 7,  Nicholas J Conley 1 7,  Gulsun Memi 1 8,  Addison N Webster 1 7,  O Yipkin Calhan 1,  Weile Liu 1,  Amani Akkoub 1,  Karan Malik 1,  Kaleigh I West 1,  Sara Michel-Le 1,  Arun Karthikeyan 1,  Grace van Gerven 1,  Olivia A Dell'Aglio 1,  Kevin T Beier 2,  Larry S Zweifel 3 4,  Manoj K Patel 5 7,  John N Campbell 1 7 9,  Christopher D Deppmann 10 11 12 13 14,  Ali D Güler 15 16 17
Affiliations

Affiliations

  • 1 Department of Biology, University of Virginia, Charlottesville, VA, USA.
  • 2 Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
  • 3 Department of Pharmacology, University of Washington, Seattle, WA, USA.
  • 4 Department of Psychiatry, University of Washington, Seattle, WA, USA.
  • 5 Department of Anesthesiology, University of Virginia, Charlottesville, VA, USA.
  • 6 Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA.
  • 7 Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA.
  • 8 Department of Physiology, School of Medicine, Adiyaman University, Adiyaman, Turkey.
  • 9 Program in Fundamental Neuroscience, University of Virginia, Charlottesville, VA, USA.
  • 10 Department of Biology, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 11 Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 12 Program in Fundamental Neuroscience, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 13 Department of Cell Biology, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 14 Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 15 Department of Biology, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 16 Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 17 Program in Fundamental Neuroscience, University of Virginia, Charlottesville, VA, USA. [email protected].
  • # Contributed equally.
PMID: 42092139 DOI: 10.1038/s41586-026-10444-4
Abstract

Glucagon-like peptide 1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes; however, established peptide-based therapies require injections and are complex to manufacture1-3. Small-molecule GLP1RAs promise oral bioavailability and scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies4-9. Here we developed humanized GLP1R mouse models to investigate how small-molecule GLP1RAs influence feeding behaviour. We found that these compounds regulate both homeostatic and hedonic feeding through parallel neural circuits. Beyond engaging canonical hypothalamic and hindbrain networks that control metabolic homeostasis, GLP1RAs recruit a discrete population of Glp1r-expressing neurons in the central amygdala, which selectively suppress the consumption of palatable foods by reducing dopamine release in the nucleus accumbens. Stimulating these central amygdalar neurons curtails hedonic feeding, whereas targeted deletion of the receptor in this cell population specifically diminishes the anorectic efficacy of GLP1RAs for reward-driven intake. These findings identify a neural circuit through which small-molecule GLP1RAs modulate reward processing, with implications for the treatment of substance-use disorder and binge eating.

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