Symmetric brain-liver circuits mediate lateralized regulation of hepatic glucose output

Hemispheric lateralization is well recognized in regulating contralateral somatic movement, yet its relevance to visceral organ regulation remains poorly understood. This study aims to investigate whether cerebral hemispheres differentially regulate hepatic glucose metabolism and localize the site of sympathetic crossover to the liver. Pseudorabies virus (PRV) tracing demonstrated symmetric projections from the paragigantocellular nucleus (LPGi) with preferential innervation of contralateral hepatic lobes. Unilateral LPGi activation elevated systemic glucose through enhanced glycogenolysis and gluconeogenesis in contralateral lobes, whereas bilateral activation produced additive effects. Following unilateral hepatic denervation, contralateral LPGi activation induced metabolic compensation in the remaining innervated lobes, characterized by increased sympathetic release, glucose production, and glycogen depletion. Whole-mount clearing and dual tracing localized the sympathetic crossover to the porta hepatis, and developmental analysis showed lobar innervation along the vasculature emerging at postnatal week 2.These findings demonstrate that the brain exerts lobe-specific, lateralized control of hepatic glucose metabolism via symmetric brain-liver sympathetic pathways. Contralateral regulation arises from peripheral decussation at the porta hepatis, and compensatory activation following denervation reveals an intrinsic neuroadaptive mechanism that safeguards systemic glucose homeostasis. HighlightsO_LIBrain-liver sympathetic projections exhibit predominant contralateral innervation C_LIO_LIUnilateral LPGi activation drives glucose production in contralateral hepatic lobes C_LIO_LIUnilateral denervation augments contralateral LPGi-mediated metabolic compensation C_LIO_LISympathetic crossover to the liver localizes at the porta hepatis C_LI