The Gut Brain Axis Introduction The ability to increase body weight is a major determinant of survival through natural selection The sensation of hunger and resultant food seeking behavior are crucial factors in human survival Hormones from the GI tract are central to this role The problem with being overweight obese is the increased risk of cardiovascular disease and cancer Neuropeptide Y NPY 36 amino acid peptide rich in tyrosine Y Causes stimulation of feeding Released after meals Similar peptide peptide YY PYY comes from the gut and appears to be able to stimulate NPY receptors in the brain Transported across the blood brain barrier to the arcuate nucleus in the hypothalamus Research aims to develop a drug that will inhibit feeding through interacting with this pathway Glucagon and glucagon like peptide 1 GLP 1 Secreted from the alpha cells of the islets of Langerhans Stimulates an increase in glucose Counter regulatory hormone to insulin cid 127 GLP 1 is formed by alternative splicing of the pre proglucagon gene Secreted by L cells of the small intestine Stimulates insulin release in response to food Responsible for the incretin effect stimulation of insulin release by indirect means After a meal pancreatic beta cells release insulin in response to glucose but also due to the concomitant release of GLP 1 cid 127 GLP 1 analogs eventide liraglutide are used to treat type 2 diabetes Role in the control of appetite Satiety fullness factor reduces feeding Reduces gastric emptying Increases transit time in the gut Blockade of GLP 1 receptors in the hypothalamus increases feeding Oxyntomodulin Inhibits acid secretion from the stomach oxyntic cells Role in the control of appetite Secreted into the bloodstream in response to a meal Proportional to caloric content Reduces appetite Leptin Produced by adipocytes Plasma concentrations correlate with fat mass cid 127 Obesity is associated with high levels of leptin Signals to the hypothalamus Specific transporters carry leptin across the blood brain barrier Very thin people have low levels of leptin cid 127 May be a marker of starvation Reduced gonadotrophin production reduced fertility Leptin may be a marker of nutrition Adequate levels of leptin signal adequate nutrition Enables reproduction Leptin may be involved in stimulating the onset of puberty Orexins Except in cases of mutation of the leptin gene in these cases leptin replacement causes normal weight in children who have extreme morbid obesity Patients who are malnourished ex anorexia nervosa are known to develop amenorrhea due to low levels of circulating gonadotrophins cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 Orexin A and orexin B stimulate food intake when administered into the lateral hypothalamus in animals cid 127 Orexin A appears to be more active Secreted by cells in the hypothalamus in response to metabolic changes and peripheral circulating gut hormones cid 127 Orexins A and B are also synthesized in the gut Role in feeding unclear Possible role in regulating the sleep wake cycle The combined effects of different gut hormones in patients with gastric bypass surgery Changes in some of the circulating gut hormones that occur after gastric bypass may be responsible for a change in appetite at the level of the hypothalamus Increase in GLP 1 and PYY production The combination of oxyntomodulin and PYY administration has recently been shown to be additive in reducing food intake cid 127 cid 127 cid 127 cid 127 cid 127 cid 127