Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states.

Summary

Single-cell analyses reveal that hepatic gluconeogenesis shifts from a periportal dominance during early fasting to include robust pericentral activity under starvation, accompanied by suppression of canonical β-catenin signaling. Starvation also reprograms glutamine metabolism, increasing glutamine incorporation into glucose.

Key Findings

• Gluconeogenic gene expression is low in fed state, increases in periportal hepatocytes during early fasting, and expands to pericentral hepatocytes under starvation.
• Starvation suppresses canonical β-catenin signaling across the lobule.
• Starvation modulates pericentral glutamine synthetase and periportal glutaminase, enhancing incorporation of glutamine into glucose.

Clinical Implications

Understanding lobule-wide plasticity of gluconeogenesis may inform interpretation of fasting tests, tracer studies, and therapeutic targeting of hepatic glucose output (e.g., modulating β-catenin pathways or glutamine flux) in diabetes and NAFLD.

Limitations

• Generalizability to human physiology requires confirmation and translational studies.
• Functional implications for whole-organ glucose production under pathologic states (e.g., insulin resistance) were not directly tested.

Future Directions

Validate zonation plasticity and β-catenin modulation in human tissues; integrate spatial omics with fluxomics in insulin resistance/NAFLD; test therapeutic modulation of glutamine-driven gluconeogenesis.