Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling.

Summary

Using zonally targeted genetic disruption of hepatic insulin signaling, the authors show periportal insulin resistance increases gluconeogenesis but paradoxically reduces lipogenesis and steatosis, whereas pericentral insulin resistance lowers pericentral steatosis without impairing glucose control. A shift of glycolytic flux from liver to muscle contributes to preserved glucose homeostasis under pericentral insulin resistance.

Key Findings

• Periportal insulin resistance increased gluconeogenesis and circulating insulin yet impaired lipogenesis and reduced HFD-induced hepatosteatosis.
• Pericentral insulin resistance decreased pericentral steatosis while maintaining normal glucose homeostasis, partly by shifting glycolytic metabolism from liver to muscle.
• Insulin exerts distinct, zone-specific roles in hepatic metabolism, implying that selective modulation of zonal signaling can uncouple steatosis from hyperglycemia.

Clinical Implications

Although preclinical, targeting pericentral hepatocyte insulin signaling or mimicking its downstream adaptations may offer strategies to attenuate hepatic steatosis without compromising glycemic control in type 2 diabetes and fatty liver disease.

Limitations

• Findings are from mouse models; translatability to humans remains to be established.
• Potential Cre driver off-target effects and limited temporal resolution were not fully addressed.

Future Directions

Test pharmacologic or genetic strategies that selectively modulate pericentral insulin signaling in larger animals and human tissues; integrate single-cell spatial omics to map downstream pathways enabling steatosis-glycemia uncoupling.