The role of vagus nerve in food-gut-brain axis. Vagal nerve manipulation as minimally invasive and reversible procedure for obesity treatment
The research question addressed in this project was “Can manipulation of abdominal vagal function and integrity be a new approach in obesity treatment?”. The hypothesis was that the vagus nerve can be the target in altering eating behaviour and energy expenditure, leading to the control of body weight. Results were as follows: 1) Truncal vagotomy: A detailed analysis of energy expenditure (EE) (total EE, resting EE and active EE) in rats subjected to vagotomy and other bariatric procedures (including gastric bypass, sleeve gastrectomy, duodenal switch and ileal transposition) have been performed, and the results have been published. 2) VNS/VBLOC: A series of VNS/VBLOC algorithms have been tested according to the effects of electric currents with different frequencies and different durations/intervals of electronic stimulation on eating behaviour over a time period of 24-48 hours. VBLOC reduced body weight by 10%, which was associated with reduced food intake, increased expression of anorexigenic neuropeptides in brainstem and hippocampus, and increased expression of hypothalamic orexigenic neuropeptides. 3) Botox: Botulinum toxin type A treatment has been tested in animals. The treatment reduced body weight by 20-30% in normal chow-fed rats, diet-induced obese (DIO) rats and DIO rats that had underwent sleeve gastrectomy. The body weight loss was associated with reduced food intake, increased energy expenditure, and increased expression of hypothalamic orexigenic neuropeptides. 4) Comparison experiments: In comparison to controls, % total weight loss (TWL) was 13% after Roux-en-Y-gastric bypass (RYGB), 16% after Omega-Loop gastric bypass (OmegaGB), 11% after sleeve gastrectomy (SG), 10% after VBLOC, and 17% after Botox. Truncal vagotomy per se was without TWL, but prevented Botox-induced %TWL. Gastric empting time (GET) was unchanged after Botox. Food intake was reduced after VBLOC or Botox. Energy expenditure was increased after Botox or OmergaGB. Meal duration (min/meal) and satiety ratio (min/g) were increased after Botox. Rate of eating (g/min) was decreased after OmegaGB. Intermeal interval (min) was increased after VBLOC. There were no mortality and surgical complications after Botox, VBLOC, and/or VTPP. However, the mortality rates were 8-36% after RYGB, GB or SG due to the experience curve effect and surgical complications. In conclusion, the study hypothesis has been tested in animal models. Throughout this project, the food-gut-brain axis has been explored as a target for new, minimally invasive obesity treatments, including vagus nerve stimulation/blocking (VNSB) and gastric Botox injections. The underlying mechanisms behind these new treatments and of currently used bariatric and metabolic surgeries such as gastric bypass, duodenal switch, sleeve gastrectomy, and ileal interposition have been studied (a figure cannot be inserted in this eRapport). The results obtained in this project has improved our understanding of the physiological mechanisms of bariatric surgery and led to the development of new, minimally invasive obesity treatments, namely blocking the gastric vagus nerve, by VNSB or Botox injection, can be used as non- or minimally invasive obesity treatment. Novel findings and methodology have not been published yet due to IPR. Priority patent application was filed on the 16th of July, 2014 (GB1412588.4). It is our intention to publish all the results and methods after the patent applicaiton is approved.
Based on the results of this project, a clinical phase II trial of Botox-treatment of obesity has been started at St. Olavs Hospital (REK-ref: 2013/1597, SLV-ref: 12/13405-4)(http://clinicaltrials.gov/show/NCT02035397).
Vagal nerve manipulation as minimally invasive and reversible procedure for obesity treatment
Our hypothesis is that the vagus nerve can be the target in altering eating behaviour and energy expenditure, leading to the control of body weight. The research question addressed in the present project is “Can manipulation of abdominal vagal function and integrity be a new approach in obesity treatment?”.
The study approach is to manipulate the vagal function and/or integrity and then study of the phenotypes. Up-to-date, we have made significant progress in all described studies.
1) Truncal vagotomy: Bilateral truncal vagotomy has insignificant effects, whereas other procedures (including gastric bypass, sleeve gastrectomy, duodenal switch and ileal transposition) have significant effects on body weight and eating behaviour in rats (see publications). In addition, we have examined mice genetically deficient of the muscarinic acetylcholine M3 receptor (M3KO), and found that the M3KO mice had a lean phenotype with higher energy expenditure and RER, and altered eating behaviour and gene expression of NPY, AgRP and leptin receptor in hypothalamus.
2) VNSB: We have tested the model of blocking the vagus nerve by electrical device (vagus nerve stimulation/blocking, VNSB) and found that the cathode induces depolarization (stimulation of the afferent fibers), while the proximal anode hyperpolarizes the membrane and imposes an anodic block on the efferent fibers. Electrophysiology probes in the rat brain showed electrical signals when VNSB was turned on. Both short- and long-term experiments show that VNSB activates afferent pathway to the brainstem and hippocampus leading to reduced food intake and body weight and suggest that the gut-brain axis in the regulation of food intake consists of the gut hormones-hypothalamus pathway as well as the vagus nerve-brainstem pathway. A manuscript has been submitted for publication.
3) Botox: We have performed a preclinical trial including110 rats (50 normal rats at 500 g BW and 60 high-fat-diet-induced obese rats at 700-800 g BW) that were subjected to Botox injection, vehicle injection, or sleeve gastrectomy followed by Botox injection, respectively. The results demonstrate the safety and efficacy of gastric injection of Botox as weight-loss surgery when it is performed alone or in combination with sleeve gastrectomy. Botox-induced BW-loss was due to reduced food intake and increased energy expenditure, which was mediated neither by paralyzing stomach per se nor via the hypothalamus-gut hormone pathway. The results of this preclinical trial have been submitted for presentation at DDW2014. A manuscript has been submitted for publication. In collaboration with St. Olav’s Hospital, we have initiated a clinical trial in which Botox treatment is used as non-invasive procedure for treatment of obesity.
4) Comparison experiments: The comparison among different bariatric surgical procedures has been done (see publications and above). In addition, the effect of bariatric surgery on lipid metabolism has been studied and the results are pending for publication in Nutrition and Diabetes. Since Botox treatment is much better than VNSB, we are conducting a comparison between Botox treatment and gastric bypass surgery (which is the golden procedure) in obese rats and mice. The animal tests will be completed before August 2014.
New strategies to control diabetes and obesity
Our research indicates two strategies: 1) Increase GLP-1 in the pancreas for diabetes, and 2) Target the vagus nerve to control food intake
During the year 2012, we have performed the following two studies and developed one protocol of clinical trial:
1. Understanding what happens after weight loss surgery may reveal new strategies to control diabetes. Most patients who undergo this massive intervention experience rapid resolution of type 2 diabetes after surgery. The "hindgut hypothesis" suggests that food in the rearranged hindgut stimulates the production a gut hormone called glucagon-like peptide 1 (GLP-1). This peptide increases production of insulin in the pancreas, and thereby has a beneficial effect on type 2 diabetes. We have established an animal model to help understand the mechanisms underlying the effects of weight loss surgery, and found evidence to support the hindgut hypothesis. The mechanisms underlying postsurgical weight loss and/or weight regain in patients still remain unclear. A major point of controversy is whether this is due to biological or behavioral factors. It has been difficult to directly and precisely measure eating behavior in humans. Using our CLAMS, we have found that the animals took more time to finish their meals. This is likely to be a beneficial behavior contributing to weight loss. This was done in collaboration with St.Olav’s Hospital. The results are published in Obesity Surgery 2013 January.
2. Role of the vagus nerve in the gut-brain axis revealed by stimulation and blockade of the gastric vagus nerve. In this study, we found that the gastric vagus nerve might regulate food intake independent of hypothalamic appetite-regulating peptides. These findings also have potential therapeutic relevance for targeting the gastric vagus nerve (via stVNS or Botox) on the treatment of obesity, anxiety/eating disorders and even Alzheimer’s disease. We are preparing a manuscript for publication. This study has been collaborated with St. Olav’s Hospital, Gothenburg University, University of Aberdeen, Oslo University Hospital, University of Murcia, Murcia, and Kyoto Pharmaceutical University.
3. Clinical study: Based on these studies, we have developed a protocol entitled “Behandling av sykelig fedme med intragastrisk injisering av Botulinum toxin A: en pilotstudie.” in collaboration with St. Olav’s Hospital (Bård Kulseng). The application is under revision after receiving comments from REK (EUDRACTNR: 2012-004381-18).
Effects of duodenal switch alone or in combination with sleeve gastrectomy on body weight and lipid metabolism in rats.
Nutr Diabetes 2014;4():e124. Epub 2014 jun 30
Eating behavior and glucagon-like peptide-1-producing cells in interposed ileum and pancreatic islets in rats subjected to ileal interposition associated with sleeve gastrectomy.
Obes Surg 2013 Jan;23(1):39-49.
Mechanistic comparison between gastric bypass vs. duodenal switch with sleeve gastrectomy in rat models.
PLoS One 2013;8(9):e72896. Epub 2013 sep 9
Regulated endocrine-specific protein 18 (RESP18) is localized to and regulated in A-like cells and G-cells in rat stomach.
Regul Pept 2012 Aug;177(1-3):53-9. Epub 2012 mai 2