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

Neural lateralization is well recognized in the control of contralateral somatic movement, yet its relevance to visceral organ regulation remains poorly understood. This study aimed to determine whether the central nervous system exerts lateralized control over hepatic glucose metabolism and to localize the site of peripheral sympathetic crossover to the liver. Pseudorabies virus (PRV) tracing revealed bilateral projections from the lateral paragigantocellular nucleus (LPGi) with preferential innervation of the contralateral hepatic lobes. Unilateral LPGi activation elevated systemic glucose by enhancing glycogenolysis and gluconeogenesis specifically 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 norepinephrine release, glucose production, and glycogen depletion. Whole-mount tissue clearing and dual viral tracing localized the sympathetic crossover to the porta hepatis. Developmental analysis showed that lobar-specific innervation along the vasculature emerges by postnatal week 2. These findings demonstrate that the brainstem can exert lobe-specific, lateralized control of hepatic glucose metabolism via bilaterally projecting brain – liver sympathetic pathways. This contralateral regulation arises from a peripheral decussation at the porta hepatis, and the compensatory activation observed after denervation reveals an intrinsic neuroadaptive mechanism that helps safeguard systemic glucose homeostasis.