Endothelial FUNDC1 regulates metabolic reprogramming and the obesity-diabetes transition through the SIRT3/GATA2/endothelin-1 axis.
Summary
Endothelial FUNDC1 is upregulated in T2DM and under overnutrition and drives a SIRT3-L nuclear export program that increases GATA2 activity and ET-1 production. EC-specific FUNDC1 deletion protects mice from HFD-induced obesity and insulin resistance and aligns with human data linking endothelial FUNDC1 to circulating ET-1.
Key Findings
- Endothelial FUNDC1 expression is elevated in diabetic conditions and correlates with plasma ET-1 in obese/T2DM patients.
- EC-specific Fundc1 deletion protects mice from HFD-induced obesity, insulin resistance, and metabolic disorders.
- Overnutrition triggers FUNDC1-dependent nuclear export of SIRT3-L, disinhibiting GATA2 and enhancing ET-1 production.
Clinical Implications
Suggests therapeutic strategies that inhibit endothelial FUNDC1 signaling or retain nuclear SIRT3-L to lower ET-1 and mitigate insulin resistance, informing cardio-metabolic disease prevention.
Why It Matters
Reveals an endothelial mitochondria-to-nucleus signaling axis that causally links vascular stress to systemic metabolic disease, nominating FUNDC1 and ET-1 signaling as druggable nodes.
Limitations
- Preclinical work without pharmacologic inhibition of FUNDC1 tested in vivo; translatability needs clinical validation.
- Potential sex- and tissue-specific differences were not fully delineated.
Future Directions
Develop small-molecule or biologic inhibitors of FUNDC1 signaling, test ET-1 modulation strategies, and evaluate endothelial-targeted interventions in early human metabolic disease.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Mechanistic preclinical evidence with supportive human tissue correlations.
- Study Design
- OTHER