Neurotensin Is Coexpressed, Coreleased, and Acts Together With GLP-1 and PYY in Enteroendocrine Control of Metabolism

• Published in: Endocrinology (Philadelphia) Vol. 157; no. 1; pp. 176 - 194
• Main Authors: Grunddal, Kaare V, Ratner, Cecilia F, Svendsen, Berit, Sommer, Felix, Engelstoft, Maja S, Madsen, Andreas N, Pedersen, Jens, Nøhr, Mark K, Egerod, Kristoffer L, Nawrocki, Andrea R, Kowalski, Timothy, Howard, Andrew D, Poulsen, Steen Seier, Offermanns, Stefan, Bäckhed, Fredrik, Holst, Jens J, Holst, Birgitte, Schwartz, Thue W
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.01.2016
• Subjects: Animals; BINDING-SITES; Biomarkers - metabolism; Bombesin - pharmacology; CELL-DIFFERENTIATION; CENTRAL-NERVOUS-SYSTEM; DEPENDENT INSULINOTROPIC POLYPEPTIDE; Endocrinology and Diabetes; Endokrinologi och diabetes; ENERGY-BALANCE; Enteroendocrine Cells - drug effects; Enteroendocrine Cells - metabolism; Enteroendocrine Cells - ultrastructure; Female; FOOD-INTAKE; GASTRIC-ACID; Gene Expression Regulation - drug effects; Genes, Reporter; Glucagon-Like Peptide 1 - genetics; Glucagon-Like Peptide 1 - metabolism; GLUCAGON-LIKE PEPTIDE-1; Humans; Ileum - drug effects; Ileum - metabolism; Ileum - ultrastructure; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - ultrastructure; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Male; Mice, Inbred C57BL; Mice, Transgenic; Neurotensin - genetics; Neurotensin - metabolism; PANCREATIC ENDOCRINE RESPONSES; Peptide Fragments - pharmacology; Peptide YY - genetics; Peptide YY - metabolism; PROXIMAL SMALL-INTESTINE; Rats, Wistar; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Red Fluorescent Protein; SECRETION; Secretory Vesicles - drug effects; Secretory Vesicles - metabolism; Secretory Vesicles - ultrastructure; Tissue Culture Techniques
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2015-1600

The 2 gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are well known to be coexpressed, costored, and released together to coact in the control of key metabolic target organs. However, recently, it became clear that several other gut hormones can be coexpressed in the intestinal-specific lineage of enteroendocrine cells. Here, we focus on the anatomical and functional consequences of the coexpression of neurotensin with GLP-1 and PYY in the distal small intestine. Fluorescence-activated cell sorting analysis, laser capture, and triple staining demonstrated that GLP-1 cells in the crypts become increasingly multihormonal, ie, coexpressing PYY and neurotensin as they move up the villus. Proglucagon promoter and pertussis toxin receptor-driven cell ablation and reappearance studies indicated that although all the cells die, the GLP-1 cells reappear more quickly than PYY- and neurotensin-positive cells. High-resolution confocal fluorescence microscopy demonstrated that neurotensin is stored in secretory granules distinct from GLP-1 and PYY storing granules. Nevertheless, the 3 peptides were cosecreted from both perfused small intestines and colonic crypt cultures in response to a series of metabolite, neuropeptide, and hormonal stimuli. Importantly, neurotensin acts synergistically, ie, more than additively together with GLP-1 and PYY to decrease palatable food intake and inhibit gastric emptying, but affects glucose homeostasis in a more complex manner. Thus, neurotensin is a major gut hormone deeply integrated with GLP-1 and PYY, which should be taken into account when exploiting the enteroendocrine regulation of metabolism pharmacologically.