Transcriptome analysis reveals organ-specific effects of 2-deoxyglucose treatment in healthy mice
Ann E Wells1, John J Wilson1, Sarah E Heuer1,2
1The Jackson Laboratory, Bar Harbor, ME, United States of America.
Objective:
Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear.
Methods:
This study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment.
Results:
PCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways.
Conclusions:
These findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.
Insights
2-deoxy-D-glucose (2DG) impacts gene function uniquely across mouse tissues, affecting pathways like mitochondrial metabolism in the heart and immunity in the gut. Understanding these systemic effects is crucial for therapeutic applications.
Area of Science:
- Molecular biology
- Systems biology
- Pharmacology
Background:
- Glycolytic inhibition using 2-deoxy-D-glucose (2DG) shows therapeutic promise for diseases like cancer, SLE, RA, and COVID-19.
- The systemic impact of 2DG on gene expression across various tissues remains largely uncharacterized.
Purpose of the Study:
- To investigate the systemic effects of 2DG on transcriptional profiles in nine different tissues of C57BL/6J mice.
- To identify tissue-specific gene expression modules and pathways modulated by 2DG treatment.
Main Methods:
- Transcriptional profiling of nine mouse tissues after 2DG administration.
- Analysis using Principal Component Analysis (PCA), Weighted Gene Co-network Analysis (WGCNA), ANOVA, and pathway analysis.
Main Results:
- PCA indicated that 2DG treatment resulted in tissue-specific transcriptional profiles.
- Six distinct, tissue-specific gene modules were identified as significantly altered by 2DG.
- 2DG predominantly impacted mitochondrial metabolism in the heart and immunological pathways in the small intestine.
Conclusions:
- 2DG exerts a systemic influence on gene function that is organ-dependent.
- The study provides critical insights into the multifaceted effects of 2DG, informing its potential therapeutic use and the need for further research into its systemic actions.
