RAF1 in AgRP neurons involved in the regulation of energy metabolism via the MAPK signaling pathway

Abstract

V-raf-leukemia viral oncogene 1 (RAF1), a serine/threonine protein kinase, is well established 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 feeding, overexpression ofRaf1in AgRP neurons led to obesity in mice characterized by increased body weight, fat mass, and impaired glucose tolerance. Conversely,Raf1knockout in AgRP neurons protected against diet-induced obesity, reducing fat mass and improving glucose tolerance. Mechanistically,Raf1activated the MAPK signaling pathway, culminating in the phosphorylation of cAMP response element-binding protein (CREB), which enhanced transcription ofAgrpandNpy. Insulin stimulation further potentiated 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 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

RAF1 / AgRP neurons / MAPK signaling pathway / CREB / obesity

Funding

This study received financial support from various sources, including the National Natural Science Foundation of China (Grant Nos. 81570774, 82070872, 92049118, and 82370854), the Junior Thousand Talents Program of China, and the Nanjing Medical University Startup Fund (All awarded to J.L.). We would also like to acknowledge the support provided by Jiangsu Province's Innovation Personal as well as Innovative and Entrepreneurial Team of Jiangsu Province (Grant No. JSSCTD2021) (All awarded to J.L.).

Acknowledgments

We sincerely appreciate Prof. Geyang Xu from Jinan University for generously providing the N42 cell line used in this study. This has been crucial for the smooth progress of our research.

Additional information

The online version contains supplementary materials available at http://www.jbr-pub.org.cn/article/doi/10.7555/JBR.39.20250114.

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