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Original Article Exendin-4(1-32)K-Capric Acid, a Glucagon-Like Peptide-1 Receptor Agonist, Suppresses Food Intake via Arcuate Pro-Opiomelanocortin Neurons
Sujin Yoo1orcid , Eun-Seon Yoo1, Jae Il Kim2, Jong-Woo Sohn1orcid

DOI: https://doi.org/10.3803/EnM.2024.2185 [Epub ahead of print]
Published online: April 14, 2025
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1Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
2School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
Corresponding author:  Jong-Woo Sohn, Tel: +82-42-350-2631, Fax: +82-42-350-2610, 
Email: jwsohn@kaist.ac.kr
Received: 23 September 2024   • Revised: 18 November 2024   • Accepted: 18 December 2024
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Abstract

Background
Glucagon-like peptide-1 (GLP-1) is an incretin known for its anti-obesity effects, and several effective drugs targeting GLP-1 receptors (GLP-1Rs) have recently been developed to treat obesity. Although GLP-1Rs are expressed by various populations of central neurons, it is still unclear which specific populations mediate the anti-obesity effects of GLP-1R agonists.
Methods
In this study, we utilized the previously reported GLP-1R agonist, exendin-4(1-32)K-capric acid (Ex-4c), and conducted whole-cell patch-clamp recordings, immunohistochemistry experiments, and in vivo food intake measurements.
Results
Our findings indicate that the appetite-suppressing effects of Ex-4c depend on pro-opiomelanocortin (POMC) neurons. Fos immunochemistry experiments and whole-cell patch-clamp recordings showed that Ex-4c activated POMC neurons in the arcuate nucleus of the hypothalamus. Additionally, we observed that Ex-4c stimulated GLP-1Rs and activated the protein kinase A (PKA)- dependent signaling pathway, which in turn closed putative adenosine triphosphate-sensitive K+ (KATP) channels, leading to the depolarization of POMC neurons.
Conclusion
Our results demonstrate that the appetite-suppressing effects of Ex-4c are mediated through the activation of arcuate POMC neurons. Furthermore, the PKA-dependent closure of putative KATP conductance is identified as the cellular mechanism responsible for the activation of POMC neurons.

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