Wnt/Wingless signaling promotes lipid mobilization through signal- induced transcriptional repression

• 成果类型: Article
• 署名作者: Liu, Mengmeng; Waduge, Rajitha-Udakara-Sampath Hemba-; Li, Xiao; Huang, Xiahe; Liu, Tzu- Hao; Han, Xianlin; Wang, Yingchun; Ji, Jun- Yuan
• 署名单位: Tulane University; Princeton University; Chinese Academy of Sciences; Institute of Genetics & Developmental Biology, CAS; University of Texas System; University of Texas at San Antonio
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9766
• DOI: 10.1073/pnas.2322066121
• 发表日期: 2024-07-09
• 关键词: radioisotopic method; fat storage; drosophila; oxidation; protein; cells; quantification; metabolism; droplets; pathways

摘要

The Wnt/Wingless signaling pathway plays critical roles in metazoan development and energy metabolism, but its role in regulating lipid homeostasis remains not fully understood. Here, we report that the activation of canonical Wnt/Wg signaling promotes lipolysis while concurrently inhibiting lipogenesis and fatty acid (3- oxidation in both larval and adult adipocytes, as well as cultured S2R+ cells, in Drosophila . Using RNA- sequencing and CUT&RUN (Cleavage Under Targets & Release Using Nuclease) assays, we identified a set of Wnt target genes responsible for intracellular lipid homeostasis. Notably, active Wnt signaling directly represses the transcription of these genes, resulting in decreased de novo lipogenesis and fatty acid (3- oxidation, but increased lipolysis. These changes lead to elevated free fatty acids and reduced triglyceride (TG) accumulation in adipocytes with active Wnt signaling. Conversely, downregulation of Wnt signaling in the fat body promotes TG accumulation in both larval and adult adipocytes. The attenuation of Wnt signaling also increases the expression of specific lipid metabolism- related genes in larval adipocytes, wing discs, and adult intestines. Taken together, these findings suggest that Wnt signaling- induced transcriptional repression plays an important role in regulating lipid homeostasis by enhancing lipolysis while simultaneously suppressing lipogenesis and fatty acid (3- oxidation. Significance The Wnt signaling pathway, often deregulated in cancer and other diseases, remains poorly understood in lipid metabolism, particularly lipid mobilization. This study reveals that active Wnt/Wg signaling potently reduces lipid accumulation in Drosophila adipocytes by boosting lipolysis and inhibiting lipogenesis and fatty acid (3- oxidation. Key Wnt target genes controlling fat storage and mobilization were identified; active Wnt signaling suppresses their transcription, while reduced Wnt signaling enhances it, thereby modulating triglyceride metabolism. Furthermore, active Wnt signaling directly represses the transcription of these lipid metabolism- related genes. These findings suggest that Wnt signaling- induced transcriptional repression regulates lipid homeostasis, balancing triglyceride storage and mobilization in Drosophila adipocytes.