Vagus nerve mediated liver-brain axis is a major regulator of the metabolic landscape in the liver

Background The liver serves as a major energetic reservoir for other tissues and its metabolic function is controlled by humoral and neural factors. The vagus nerve innervating the gastrointestinal tract plays an important role in regulating peripheral metabolism and energy expenditure. Although the liver receives vagus nerve fibers, the impact of this circuitry in the regulation of hepatic metabolism is still poorly understood. Methods Herein, we used a combination of quantitative proteomics and in vivo imaging techniques to investigate the impact of the vagus nerve on liver metabolism. Results Vagus nerve shapes the metabolic framework of the liver, as surgical ablation (vagotomy; VNX) of this circuitry led to a significant alteration of the hepatic proteome landscape. Differential protein expression and pathway enrichment analyses showed that glycolytic and fatty acid biosynthesis were increased following VNX, whereas β-oxidation was decreased. This metabolic shift facilitated lipid accumulation in hepatocytes. Furthermore, VNX worsened liver steatosis following high-carbohydrate or high-fat dietary challenges. Conclusions This study describes the liver-brain axis mediated by the vagus nerve as an important regulator of the hepatic metabolic landscape. Highlights ### Competing Interest Statement The authors have declared no competing interest. * ZT : Zeitgeber Time TEAB : Triethylammonium Bicarbonate TCEP : Tris(2-carboxyethyl)phosphine Hz : Hertz ACN : Acetonitrile TFA : Trifluoroacetic Acid VNX : Vagotomy MS : Mass Spectometry HCD : High-carbohydrate diet HFD : High-fat diet KEGG : Kyoto Encyclopedia of Genes and Genomes TCA : Tricarboxylic Acid Cycle DMSO : dimethyl sulfoxide Gck : Glucokinase Pfkl : Phosphofructokinase Aldob : Aldolase, fructose-bisphosphate B Pklr : Pyruvate kinase liver and red blood cell Fasn : Fatty acid synthase Acaca : Acetyl-Coenzyme A carboxylase alpha Acacb : Acetyl-Coenzyme A carboxylase beta Mcat : Malonyl CoA:ACP acyltransferase (mitochondrial) Scd1 : Stearoyl-Coenzyme A desaturase 1 Acot1 : Acyl-CoA thioesterase 1 Hsd17b12 : hydroxysteroid (17-beta) dehydrogenase 12 Cyp4a14 : Cytochrome P450, family 4, subfamily a, polypeptide 14 Acox1 : Acyl-Coenzyme A oxidase 1, palmitoyl Acaa1a : Acetyl-Coenzyme A acyltransferase 1A Fbp1 : Fructose bisphosphatase 1 Pck1 : Phosphoenolpyruvate carboxykinase 1, cytosolic NAFLD : Non-Alcoholic Fatty Liver Disease NASH : Non-Alcoholic Steatohepatitis NTS : Nucleus of the solitary tract DMN : Dorsal motor nucleus of the vagus NA : Ambiguus nucleus PCA : Principal Component Analysis FDR : False Discovery Rate