Abstract Body: Background:
Endothelial cells (ECs) actively regulate systemic metabolic homeostasis, yet how endothelial nucleotide metabolism contributes to cardiometabolic disease remains poorly defined. ATIC, a key enzyme in de novo purine synthesis, has been implicated in metabolic stress responses, but its endothelial-specific role in obesity-associated metabolic dysfunction is unknown.
Methods:
We generated endothelial cell-specific ATIC knockout mice and subjected cohorts to a high-fat diet (HFD) to induce metabolic stress. Body composition was measured by nuclear magnetic resonance (NMR). Glucose homeostasis and insulin sensitivity were assessed using glucose tolerance tests (GTT) and insulin tolerance tests (ITT). Whole-body energy balance was evaluated using comprehensive laboratory animal monitoring system (CLAMS) metabolic cages. Hepatic steatosis and adipose tissue inflammation were assessed by histology and inflammatory marker expression. Adipose angiogenesis was quantified, and acute inflammatory responsiveness was examined.
Results:
Under HFD, endothelial ATIC deficiency decreased fat mass and increased lean mass, accompanied by improved glucose tolerance and insulin sensitivity. CLAMS profiling indicated altered whole-body energy balance consistent with improved metabolic efficiency. At the tissue level, endothelial ATIC deletion attenuated hepatic steatosis and reduced adipose tissue inflammation. Notably, these metabolic benefits occurred without changes in adipose angiogenesis, indicating improved metabolic outcomes independent of vascular expansion. In contrast, endothelial ATIC deficiency did not alter acute TNF-induced inflammatory responses in vivo, suggesting a selective role in chronic metabolic inflammation rather than cytokine-driven acute inflammatory signaling.
Conclusions:
These findings identify endothelial ATIC-dependent purine metabolism as a previously unrecognized regulator of HFD-induced cardiometabolic dysfunction and fatty liver disease, supporting endothelial nucleotide metabolism as a potential therapeutic entry point for metabolic disease with vascular involvement.