V-raf-leukemia viral oncogene 1(RAF1), a serine/threonine protein kinase, is universally acknowledged to play a crucial role in tumorigenesis and cell development. However, the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown. In this study, we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet induced obesity (DIO) mice. Under normal chow diet (NCD) feeding, over-expression of Raf1 in AgRP neurons leads to obesity in mice characterized by increased body weight, fat mass, and impaired glucose tolerance. Conversely, knock-out of the Raf1 gene in AgRP neurons protects against DIO, reducing fat mass and improving glucose tolerance. Mechanistically, Raf1 activates the MAPK signaling pathway, culminating in cAMP response element-binding protein (CREB) phosphorylation, which enhances transcription of Agrp and Npy. Insulin stimulation further potentiates the RAF1-MEK1/2-ERK1/2-CREB axis, highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance. Collectively, these findings underscore the important role of RAF1 in AgRP neurons in maintaining the energy homeostasis and obesity pathogenesis, positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.

Keywords: AgRP neurons; CREB; MAPK signaling pathway; RAF1; obesity.

丝裂原活化蛋白激酶1（RAF1）是一种丝氨酸/苏氨酸蛋白激酶，在肿瘤发生和细胞发育中起着至关重要的作用。然而，下丘脑中RAF1在调节能量代谢中的具体作用尚不清楚。在这项研究中，我们发现饮食诱导的肥胖（DIO）小鼠下丘脑AgRP神经元中RAF1的表达显著增加。在正常饲料喂养条件下，AgRP神经元中Raf1过表达会导致小鼠出现体重增加、脂肪质量增加和糖耐量受损的现象。相反，在AgRP神经元中敲除Raf1基因可以抵抗DIO的发生，减少脂肪质量和改善糖耐量。机制上，Raf1激活了MAPK信号通路，最终导致cAMP反应元件结合蛋白（CREB）磷酸化，这增强了Agrp和Npy的转录。胰岛素刺激进一步强化了RAF1-MEK1/2-ERK1/2-CREB轴，突出了RAF1在整合激素和营养信号以调节能量平衡中的作用。总的来说，这些发现强调了RAF1在AgRP神经元中维持能量稳态和肥胖发病机制中的重要角色，并将其及其下游通路定位为对抗肥胖及相关代谢疾病的创新策略的潜在治疗靶点。

关键词： AgRP神经元；CREB；MAPK信号通路；RAF1；肥胖。