The appetite-suppressing effects of Ex-4c are mediated through the activation of neurons.
Ex-4c activates pro-opiomelanocortin (POMC) neurons located in the arcuate nucleus of the hypothalamus.
Fos immunochemistry and whole-cell patch-clamp recordings confirmed the activation of POMC neurons by Ex-4c.
Ex-4c stimulates GLP-1 receptors and activates a signaling pathway that involves protein kinase A (PKA).
The PKA-dependent signaling leads to the closure of KATP channels, resulting in depolarization of POMC neurons.
Simplified
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 () 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.
Key numbers
0.32 μg
Median Effective Dose for Food Intake Suppression
Dose of Ex-4c required for significant food intake reduction.
242±10
Neuron Count Post-Ablation
Average number of β-endorphin positive neurons in iDTR::-Cre mice.
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