Liver-innervating vagal sensory neurons are indispensable for the development of hepatic steatosis and anxiety-like behavior in diet-induced obese mice.

Summary

Selective disruption of liver-innervating vagal sensory neurons in mice increased energy expenditure, prevented diet-induced obesity, attenuated hepatic steatosis, and reduced anxiety-like behavior. Glucose homeostasis improved in both sexes, with male-specific gains in insulin sensitivity, highlighting a bidirectional liver–brain control of metabolic and behavioral phenotypes.

Key Findings

• Ablation of liver-projecting vagal sensory neurons prevented diet-induced obesity by increasing energy expenditure.
• Loss of these neurons limited hepatic steatosis and improved glucose homeostasis; male mice had increased insulin sensitivity.
• Neuronal loss also reduced anxiety-like behavior, implicating the liver–brain axis in metabolic and behavioral regulation.

Clinical Implications

Although preclinical, targeting the liver–brain vagal axis (e.g., selective neuromodulation or peripheral afferent modulation) could complement metabolic therapies for MASLD and address anxiety comorbidity in obesity.

Limitations

• Mouse model findings require validation in humans to confirm translational relevance.
• Molecular signals from liver to brain were not fully delineated.

Future Directions

Define molecular mediators of the liver–brain signal, test neuromodulatory interventions, and conduct human studies to evaluate biomarkers and translational feasibility.