Oral Presentation ANZOS-OSSANZ-AOCO Joint Annual Scientific Meeting 2017

Using human tissue to understand the relevance of the gut endocrine system in obesity (#26)

Damien Keating 1
  1. Flinders University, Adelaide, SA, Australia

Gut endocrine cells (called enteroendocrine cells) are scattered amongst the gastrointestinal epithelium and collectively constitute the largest endocrine tissue in our body. They consist of an array of different cell types, each synthesising different peptide hormones. Many of these hormones have significant effects on metabolism, food intake and body weight. Our studies have focused on cells that release GLP-1, PYY and serotonin (5-HT). We have combined secretion studies using ex vivo tissue from human colon, ileum and duodenum with in vivo studies in lean, obese and type 2 diabetes individuals. Gut-derived 5-HT suppresses thermogenesis in mice and causes obesity. We have identified that gut-derived 5-HT increases in obese humans, and that gut 5-HT acts as a link between the gut microbiome and host obesity. GLP-1 is an incretin hormone and, along with PYY, can regulate central pathways associated with food intake. We have elucidated the pathway by which glucose triggers GLP-1 secretion in human small intestine and identified that the melanocortin pathway, typically associated with central pathways controlling food intake, also exists within the gut epithelium and activates GLP-1 and PYY secretion in human gut via the MC4 receptor. Metformin is the most widely prescribed diabetes drug in the world and has moderate effects in reducing body weight. Our combined clinical and ex vivo studies demonstrate that metformin triggers GLP-1 and PYY secretion in human gut, and that metformin-induced GLP-1 secretion is responsible for 75% of the glucose lowering effect of metformin. Such findings indicate that the mechanisms controlling peripheral gut hormone secretion have direct relevance to metabolic control and human obesity in a number of different ways.