Kim Nayoun, Kim Eun-Kyoung
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea.
Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea.
Mol Brain. 2025 Jun 10;18(1):49. doi: 10.1186/s13041-025-01220-y.
Hypothalamic neuropeptides play a pivotal role in regulating appetite and energy homeostasis. Extracellular ATP, a key signaling molecule in the hypothalamus, is associated with neuronal activity and metabolic processes. However, its role in appetite control remains unclear. This study explored how sustained extracellular ATP regulates the expression of hypothalamic orexigenic neuropeptides Agrp and Npy. The administration of ATP alone reduced food intake, body weight, and orexigenic neuropeptide expression in mice. Conversely, inhibition of ATP conversion into AMP using the ectonucleoside triphosphate diphosphohydrolase inhibitor ARL67156 caused a transient increase in these parameters. Prolonged extracellular ATP was shown to upregulate Agrp and Npy expression via purinergic P2X4 receptor (P2X4R) activation in AGRP/NPY-expressing cells. Activation of P2X4R induced CaMKII phosphorylation, which subsequently led to CREB phosphorylation and upregulation of orexigenic neuropeptides. Our findings reveal a mechanism whereby extracellular ATP accumulation promotes appetite through P2X4R-CaMKII-CREB signaling, shedding light on how extracellular ATP impacts hypothalamic appetite control.
下丘脑神经肽在调节食欲和能量平衡方面起着关键作用。细胞外ATP是下丘脑中的一种关键信号分子，与神经元活动和代谢过程相关。然而，其在食欲控制中的作用仍不清楚。本研究探讨了持续的细胞外ATP如何调节下丘脑促食欲神经肽Agrp和Npy的表达。单独给予ATP可降低小鼠的食物摄入量、体重和促食欲神经肽的表达。相反，使用外核苷酸三磷酸二磷酸水解酶抑制剂ARL67156抑制ATP转化为AMP会导致这些参数短暂增加。研究表明，在表达AGRP/NPY的细胞中，延长细胞外ATP通过嘌呤能P2X4受体（P2X4R）激活上调Agrp和Npy的表达。P2X4R的激活诱导CaMKII磷酸化，随后导致CREB磷酸化和促食欲神经肽的上调。我们的研究结果揭示了一种机制，即细胞外ATP积累通过P2X4R-CaMKII-CREB信号传导促进食欲，阐明了细胞外ATP如何影响下丘脑食欲控制。
