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

ABSTRACT: The Wnt/Wingless signaling pathway plays critical roles in metazoan development and energy metabolism, but its involvement in lipid mobilization has remained unclear. Here, we report that canonical Wnt/Wg signaling reduces lipid accumulation in both larval and adult adipocytes, as well as cultured S2R+ cells, in Drosophila. This reduction occurs through promoting lipolysis while concurrently repressing lipogenesis and fatty acid β-oxidation. Leveraging RNA-sequencing and CUT&RUN assays, we have 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 triglyceride accumulation in lipid droplets, increased lipolysis, and reduced fatty acid β-oxidation. These changes lead to elevated free fatty acids and reduced triglyceride accumulation in adipocytes with active Wnt signaling. Conversely, downregulation of Wnt signaling in the fat body promotes triglyceride accumulation in both larval and adult stages. The attenuation of Wnt signaling also increases the expression of specific lipid metabolism-related genes in larval adipocytes, wing discs, and adult intestines. Collectively, our 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 β-oxidation processes.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE264356 | GEO | 2024/06/18

REPOSITORIES: GEO

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Project description:CPT1B, as the major rate-limiting enzyme for fatty acid β-oxidation, involved in the regulation of adipose tissue lipid deposition, but its role in the regulation of goat intramuscular fat (IMF) remains unclear. Here, we conducted knockdown experiments targeting the CPT1B gene in goat intramuscular preadipocytes, resulting in a significant increase in intracellular triglyceride (TAG) content and lipid droplet accumulation. Conversely, the overexpression of CPT1B led to a significant decrease in intracellular TAG content and lipid droplet accumulation. Mechanistically, through RNA-seq analysis of CPT1B knockdown samples, we identified 285 differentially expressed genes (DEGs), including 71 up-regulated and 214 down-regulated genes. Notably, these DEGs were significantly enriched in various KEGG signaling pathways, such as fatty acid metabolism, focal adhesion, FoxO signaling, PI3K-Akt signaling, and MAPK signaling pathways. Gene Set Enrichment Analysis (GSEA) further confirmed the upregulation of the MAPK signaling pathway upon CPT1B knockdown in adipocytes. In rescue experiments, we demonstrated that the addition of a p38MAPK inhibitor (PD169316) to CPT1B-knockdown adipocytes counteracted the increase in lipid deposition caused by the loss of CPT1B function. These findings suggest that CPT1B inhibits lipid deposition in goat intramuscular preadipocytes via the p38MAPK signaling pathway. In addition, we observed a potential interaction between CPT1B and CPT1A through Protein-Protein Interaction Networks (PPIs). Interestingly, CPT1A exhibited a similar regulatory function to CPT1B, and they both were able to partially restore the changes in lipid deposition induced by each other. This observation supports the hypothesis of synergistic effects between CPT1B and CPT1A. Collectively, our results elucidate the role of CPT1B in the regulation of lipid deposition in goat intramuscular adipocytes through the p38MAPK signaling pathway, providing valuable insights for enhancing the quality of goat intramuscular fat.

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

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