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Exendin-4(1-32)K-Capric Acid, a Glucagon-Like Peptide-1 Receptor Agonist, Suppresses Food Intake via Arcuate
Sujin Yoo1, Eun-Seon Yoo1, Jae Il Kim2
1Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Backgruound:
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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