bioRxiv : the preprint server for biologyJan 7, 2025

A Brain Reward System Suppressed by New Weight Loss Drugs

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 20, 2026

Abstract

Small-molecule GLP1RAs engage a dedicated neural circuit that influences feeding behavior.

These compounds regulate both homeostatic and hedonic feeding through parallel neural circuits.
They activate neurons in the central amygdala that suppress palatable food consumption by reducing dopamine release in the nucleus accumbens.
Stimulating central amygdalar neurons decreases hedonic feeding.
Targeted deletion of the receptor in this neuron population reduces the appetite-suppressing effects of GLP1RAs on reward-driven intake.
The findings suggest potential applications for treating conditions related to dopamine dysregulation, such as substance use disorder and binge eating.

Simplified

Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes, yet established peptide-based therapies require injections and complex manufacturing. Small-molecule GLP1RAs promise oral bioavailability and scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. Here, we developed humanized GLP1R mouse models to investigate how small-molecule GLP1RAs influence feeding behavior. This approach revealed 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 curtail 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 reveal a dedicated neural circuit through which small molecule GLP1RAs modulate reward processing, suggesting broad therapeutic potential in conditions of dysregulated dopamine signaling including substance use disorder and binge eating.

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A Brain Reward System Suppressed by New Weight Loss Drugs

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