2. Academic Validation
  3. The central amygdala gates exogenous glucagon-like peptide 1 signals

The central amygdala gates exogenous glucagon-like peptide 1 signals

  • Mol Metab. 2026 Jun 18:110:102403. doi: 10.1016/j.molmet.2026.102403.
Miguel Duran 1,  Ningxiang Zeng 2,  Elam J Cutts 2,  Anusha Polamarasetty 2,  Melissa Rodriguez 2,  Kirk M Habegger 3,  J Andrew Hardaway 4
Affiliations

Affiliations

  • 1 Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: [email protected].
  • 2 Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 3 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 4 Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: [email protected].
PMID: 42314903 DOI: 10.1016/j.molmet.2026.102403
Abstract

Nuclei within the limbic system like the central amygdala (CeA) play a critical role in mediating fear, motivation, reward, and appetitive behavior. Although previous reports demonstrate the presence of the glucagon-like peptide-1 receptor (GLP-1R) in limbic nuclei, how limbic neurons mediate the actions of systemically administrated GLP-1R agonists is unclear. In this study, we investigated the CeA's response to peripherally administered GLP-1R agonist Exendin-4 (Ex-4) in vivo, and determined the functional requirement of select CeA neuron populations in acute Ex-4 induced hypophagia. Using fiber photometry, we observed that Ex-4 promoted a rapid and lasting activation of CeA neurons that was blocked by pretreatment with the GLP-1R antagonist Exendin-9. We then tested the functional requirement of CeA neuron activation in mediating Ex-4 induced hypophagia of standard grain chow using inhibitory chemogenetics. Chemogenetic inhibition of all CeA neurons significantly suppressed the hypophagic actions of Ex-4. Then using selective mouse Cre-drivers, we found that chemogenetic inhibition of protein kinase c delta (PrkcdCeA) and GLP-1R (Glp1rCeA), but not somatostatin (SstCeA), neurons also attenuates the full hypophagic effect of Ex-4. Having observed that inhibition of Glp1rCeA modestly attenuated Ex-4 induced hypophagia of standard chow, we then tested whether these neurons might mediate Ex-4 suppression of energy-dense, palatable diet. We used intermittent high-fat diet (HFD) access and found that inhibition of Glp1rCeA neurons significantly rescued the reduction of HFD consumption by Ex-4. Collectively, these data demonstrate that the CeA responds to peripherally administered GLP-1R agonists and that multiple CeA neuron populations are required for the complete effect of GLP-1R agonist mediated hypophagia.

Keywords

Central amygdala; Chemogenetics; Exendin-4; Fiber photometry; GLP-1 receptor.

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