Liver-innervating vagal sensory neurons play an indispensable role in the development of hepatic steatosis and anxiety-like behavior in mice fed a high-fat diet.

BACKGROUND AND AIMS: The visceral organ-brain axis, mediated by vagal sensory neurons in the vagal nerve ganglion, is essential for maintaining various physiological functions. In this study, we investigated the impact of liver-projecting vagal sensory neurons on energy balance, hepatic steatosis, and anxiety-like behavior in mice under obesogenic conditions.

METHODS: We performed single-nucleus RNA sequencing of vagal sensory neurons innervating the liver. Based on our snRNA-Seq results, we used the Avil CreERT2 strain to identify vagal sensory neurons that innervate the liver.

RESULTS: A small subset of polymodal sensory neurons innervating the liver was located in the left and right ganglia, projecting centrally to the nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus, and peripherally to the periportal areas in the liver. Male and female control mice developed diet-induced obesity (DIO) during high-fat diet feeding. Deleting liver-projecting advillin-positive vagal sensory neurons prevented DIO in male and female mice, and these outcomes are associated with increased energy expenditure. Although males and females exhibited improved glucose homeostasis following disruption of liver-projecting vagal sensory neurons, only male mice displayed increased insulin sensitivity. The loss of liver-projecting vagal sensory neurons limited the progression of hepatic steatosis in male and female mice fed a steatogenic diet. Finally, mice lacking liver-innervating vagal sensory neurons exhibited less anxiety-like behavior compared to the control mice.

CONCLUSIONS: The liver-brain axis contributes to the regulation of energy balance, glucose tolerance, hepatic steatosis, and anxiety-like behavior depending on the nutrient status in healthy and obesogenic conditions.