Mechanisms of activation of mouse and human enteroendocrine cells by nutrients

Abstract

ObjectiveInhibition of food intake and glucose homeostasis are both promoted when nutrients stimulate enteroendocrine cells (EEC) to release gut hormones. Several specific nutrient receptors may be located on EEC that respond to dietary sugars, amino acids and fatty acids. Bypass surgery for obesity and type II diabetes works by shunting nutrients to the distal gut, where it increases activation of nutrient receptors and mediator release, but cellular mechanisms of activation are largely unknown. We determined which nutrient receptors are expressed in which gut regions and in which cells in mouse and human, how they are associated with different types of EEC, how they are activated leading to hormone and 5-HT release.Design and resultsmRNA expression of 17 nutrient receptors and EEC mediators was assessed by quantitative PCR and found throughout mouse and human gut epithelium. Many species similarities emerged, in particular the dense expression of several receptors in the distal gut. Immunolabelling showed specific colocalisation of receptors with EEC mediators PYY and GLP-1 (L-cells) or 5-HT (enterochromaffin cells). We exposed isolated proximal colonic mucosa to specific nutrients, which recruited signalling pathways within specific EEC extracellular receptor-regulated kinase (p-ERK) and calmodulin kinase II (pCAMKII), as shown by subsequent immunolabelling, and activated release of these mediators. Aromatic amino acids activated both pathways in mouse, but in humans they induced only pCAMKII, which was colocalised mainly with 5-HT expression. Activation was pertussis toxin-sensitive. Fatty acid (C12) potently activated p-ERK in human in all EEC types and evoked potent release of all three mediators.ConclusionsSpecific nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes.

Intraduodenal infusion of a combination of tastants decreases food intake in humans

“…Infusion of the other single tastants did not modulate feelings of satiety or of food intake. Plasma concentrations of gastrointestinal peptides that are generally considered to play a role in the control of food Several studies reported previously on the expression of taste receptor type 1, taste receptor type 2, and other taste signaling proteins in several parts of the small and large intestine (7,8,16). Activation of these taste receptors, expressed on enteroendocrine cells, may trigger release of several gastrointestinal peptides, including cholecystokinin, GLP-1, and PYY.…”

Critical review evaluating the pig as a model for human nutritional physiology

“…The threshold values for humans refer to the lowest concentration tested following the ascending forced choice triangle test method (Newman & Keast (331) ), which resulted in significant (P < 0·05) detection (E Roura, unpublished results). Pig: tongue (31,334,335) ; stomach, jejunum (51) Human: spermatozoa, testis (336) ; stomach (337) ; liver, HuCCT1 cells (338) ; pancreatic Min6 cells, H9C2 cells and HeLa cells (339) ; tongue fungiform papillae (340) ; adrenal, brain, breast, colon, heart, kidney, lung, ovary, skeletal muscle, testis, thyroid (341) ; stomach antrum, duodenum, proximal jejunum, mid-jejunum, colon, rectum (342) ; pancreas, liver (343) ; intestinal endocrine cells (344) ; GLP-1-producing cells (345) Other: evolutionary analysis (pig) (45) ; sequencing, cloning, cell reporter system (pig) (4,48) TAS1R2…”

“…Sweet 84/76 Carbohydrates (314) , for example: sucrose, saccharin, dulcin and acesulfame-K (346) ; aspartame, cyclamate (347) Pig: tongue (31,334,335) ; small intestine (348) Human: stomach (337) ; duodenum, NCI-H716 cells and GLP-1-producing cells (345) ; liver, HuCCT1 cells (338) ; duodenum, jejunum (349) ; HeLa cells, DU145 cells (350) ; bladder urothelium (351) ; skeletal muscle (341) ; duodenum, jejunum (342) ; tongue (352) Other: evolutionary analysis (pig) (45)…”

What goes around comes around: novel pharmacological targets in the gut–brain axis

“…Specific nutrient receptors in EECs are associated with distinct signaling pathways and lead to the release of a variety of mediators. For example, the protein breakdown product receptor GPR93 and the short-chain fatty-acid receptor FFAR2 are highly expressed in EECs of human and mouse large intestine [Symonds et al 2015]. Upon nutrient activation, the release of neuroactive molecules such as 5-HT and PYY is also differentially modulated [Symonds et al 2015].…”

“…Among them, enteroendocrine cells (EECs), located at the base of intestinal crypts, transduce mechanic and chemical signals from the intestinal lumen to neighbor cells and the local neuronal network in a paracrine/endocrine fashion [Crowell, 2004;Symonds et al 2015]. Specific nutrient receptors in EECs are associated with distinct signaling pathways and lead to the release of a variety of mediators.…”