Ablation of parasympathetic cholinergic innervation of the liver prevents diet-induced obesity and hepatic steatosis in mice.

The role of parasympathetic cholinergic innervation in hepatic lipid metabolism has been the subject of considerable debate because of a lack of neuroanatomical studies. We investigate the impact of the loss of function of parasympathetic cholinergic innervation to the liver on hepatic lipid metabolism in mice fed a high-fat diet (HFD). Our results, obtained through immunostaining and 3D imaging of cleared liver tissue, reveal the presence of muscarinic acetylcholine receptors and parasympathetic nerve originating from the dorsal motor nucleus of the vagus in hepatocytes. Deleting this innervation reduces body weight and increases energy expenditure. Ablating these neurons prevents hepatic steatosis and leads to browning of inguinal white adipose tissue. Loss of hepatic cholinergic input increases hepatic Cyp7b1 expression and serum bile acid levels. Knockdown of the G protein-coupled bile acid receptor 1 gene in inguinal white adipose tissue reverses the beneficial effects of the loss of hepatic cholinergic function on hepatic steatosis. These findings suggest that modulating the parasympathetic cholinergic innervation of the liver may offer a therapeutic avenue for restoring lipid metabolism in obesity and diabetes. ### Competing Interest Statement The authors have declared no competing interest.