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

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

Introduction

Obesity and metabolic dysfunction-associated fatty liver disease (MAFLD) are frequently comorbid with psychiatric conditions such as anxiety. However, the mechanistic links between metabolic and behavioral dysregulation remain poorly defined. A recent study by Hwang et al. (2025) employed spatially resolved transcriptomics to investigate how liver-innervating vagal sensory neurons contribute to both hepatic steatosis and anxiety-like behaviors in a mouse model of diet-induced obesity.

Let’s Talk about Your NGS Project

Methodological Approach

The study utilized the 10x Genomics Visium Spatial Gene Expression platform to analyze cryosectioned liver tissues from high-fat diet (HFD)-fed mice. Graph-based clustering and established zonation markers (e.g., Gstm3 for pericentral, Cdh1 for periportal regions) enabled precise identification of distinct hepatic zones: pericentral, mid-zone, and periportal. This spatial approach was integrated with functional validation to correlate gene expression patterns with metabolic and behavioral phenotypes.

Key Findings

Neural Circuit Mapping via Spatial Transcriptomics

Spatial transcriptomic analysis revealed that liver-innervating vagal sensory neurons predominantly innervate periportal regions—areas critical for processing gut-derived nutrients and hormones. These neurons expressed receptors for mechanical and nutrient sensing (e.g., Piezo channels, TRPV1, and cholecystokinin receptors), highlighting their role as multimodal sensors of hepatic metabolic status.

Zonation-Specific Metabolic Insights

Disruption of vagal liver innervation markedly reduced hepatic steatosis and diet-induced obesity. Spatial transcriptomics enabled zone-specific functional annotation:

Periportal regions were associated with terms such as "increased liver weight,"
Mid-zones showed enrichment for "abnormal hepatocyte morphology,"
Pericentral regions were linked to "abnormal circulating amino acid levels."

These findings were supported by downregulation of key lipogenic genes (Srebf1, Fasn, Scd1) and the fatty acid transporter Cd36, demonstrating a zonated regulatory mechanism underlying the observed metabolic phenotypes.

Behavioral Correlates

Mice with ablated liver-vagal sensory innervation exhibited significantly reduced anxiety-like behavior. This suggests that vagal sensory pathways not only regulate hepatic lipid metabolism but also modulate brain circuits involved in affective behavior, thereby establishing a functional liver-brain axis.

Conclusion

The application of spatial transcriptomics in this study provided unprecedented resolution in mapping neural-hepatic interactions across anatomically distinct liver zones. By revealing how vagal sensory neurons coordinate zonated metabolic and behavioral responses to obesogenic diets, this work establishes a new framework for targeting the liver-brain axis in the treatment of MAFLD and its psychiatric comorbidities.

References

Hwang, J., Lee, S., Okada, J. et al. Liver-innervating vagal sensory neurons are indispensable for the development of hepatic steatosis and anxiety-like behavior in diet-induced obese mice. Nat Commun 16, 991 (2025). https://doi.org/10.1038/s41467-025-56328-5

Let’s Talk about Your NGS Project

(Fields marked with an * are required)

First Name*

Last Name*

Email Address*

Institution/Organization*

Country/Region*

State*

Tell us more about your project or service of interest.*

Novogene Corporation Inc.

2921 Stockton Blvd. Suite 1810, Sacramento CA 95817

916-252-0068 inquiry@novogeneusa.com www.novogene.com