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

Author:

Grunddal Kaare V.12,Ratner Cecilia F.12,Svendsen Berit13,Sommer Felix4,Engelstoft Maja S.125,Madsen Andreas N.12,Pedersen Jens13,Nøhr Mark K.12,Egerod Kristoffer L.12,Nawrocki Andrea R.6,Kowalski Timothy6,Howard Andrew D.6,Poulsen Steen Seier3,Offermanns Stefan7,Bäckhed Fredrik14,Holst Jens J.13,Holst Birgitte12,Schwartz Thue W.12

Affiliation:

1. Novo Nordisk Foundation Center for Basic Metabolic Research (K.V.G., C.F.R., B.S., M.S.E., A.N.M., J.P., M.K.N., K.L.E., F.B., J.J.H., B.H., T.W.S.), Copenhagen DK-2200, Denmark

2. Section for Metabolic Receptology and Enteroendocrinology; Laboratory for Molecular Pharmacology (K.V.G., C.F.R., M.S.E., A.N.M., M.K.N., K.L.E., B.H., T.W.S.), Copenhagen DK-2200, Denmark

3. Department of Neuroscience and Pharmacology; and Department of Biomedical Sciences (B.S., J.P., S.S.P., J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark;

4. Department of Molecular and Clinical Medicine (F.S., F.B.), Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, University of Gothenburg, 413 45 Gothenburg, Sweden

5. Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark

6. Merck Research Laboratories (A.R.N., T.K., A.D.H.), Kenilworth, NJ 07033

7. Department of Pharmacology (S.O.), Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany

Abstract

Abstract 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.

Publisher

The Endocrine Society

Subject

Endocrinology

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