The Role of Vagus Nerve in The Brain-Gut Axis: A Target for Obesity Treatment

Background/aim: Vagal communication between the gut and brain is involved in the control of body weight and can be a new target for obesity treatments. The aim of this study was to develop new therapeutic approaches of blocking the gastric vagus nerve by electrical device or Botox injection. Methods: Rats received vagus nerve stimulation/blocking (VNSB) at the site of the subdiaphragmatic trunks by an electrical device or Botulinum toxin type A (Botox) injection in the gastric antrum. In addition, muscarinic M3 receptor knockout mice were examined. In these animal models body weight, food intake, eating behavior, metabolic parameters, gut hormone concentrations, gastric acid secretion, gastric emptying and the expression profile of energy balance-regulating genes in the hypothalamus and brainstem were examined. Comprehensive Laboratory Animal Monitoring System (CLAMS) was used, and gene expression was analyzed by in situ hybridization, low density array and RNA-Seq. Results: Short-term VNSB (48 h) increased gene expression of orexigenic neuropeptides in hypothalamus (neuropeptide Y (NPY) and agouti-related peptide (AgRP)), but was without effects on gastric acid secretion and food intake. Long-term VNSB (6-8 weeks) increased orexigenic gene expression in hypothalamus (NPY, forkhead box protein A2), and anorexigenic gene expression in the brainstem (leptin and CCK2 receptors). Food intake and body weight was reduced by 30 and 10%, respectively. In the hippocampus, VNSB increased the expression of CCK, somatostatin and tyrosine hydroxylase. 48 h after Botox injection no parameters were changed, but long-term Botox treatment reduced food intake and body weight by 32 and 17%, respectively. This was reproducible in diet-induced obese rats, and in rats previously subjected to sleeve gastrectomy. At 2 months after starting Botox treatment, hypothalamic NPY expression was upregulated and pro-opiomelanocortin (POMC) downregulated. Interestingly, Botox injection did not affect gastric emptying. M3 receptor knockout mice had upregulated hypothalamic NPY, AgRP and leptin receptor expression, but a lean phenotype with increased energy expenditure. Conclusions: The present study provides evidence for important roles of gastric vagus nerve in the brain-gut axis. Blocking the gastric vagus nerve by VNSB, Botox injection and knockout of M3 receptor can be used for treatment of obesity.