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

Endocrinology - Tập 157 Số 1 - Trang 176-194 - 2016
Kaare V. Grunddal1,2,3, Cecilia Ratner1,2,3, Berit Svendsen4,5,1, Felix Sommer6, Maja S. Engelstoft7,1,2,3, Andreas Nygaard Madsen1,2,3, Jens Pedersen4,5,1, Mark K. Nøhr1,2,3, Kristoffer L. Egerod1,2,3, Andrea R. Nawrocki8, Timothy J. Kowalski8, Andrew W. Howard8, Steen Seier Poulsen4,5, Stefan Offermanns9, Fredrik Bäckhed6,1, Jens J. Holst4,5,1, Birgitte Holst1,2,3, Thue W. Schwartz1,2,3
1Novo 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
2Section for Metabolic Receptology and Enteroendocrinology
3Section 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
4Department of Neuroscience and Pharmacology
5Department 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;
6Department 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
7Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark
8Merck Research Laboratories (A.R.N., T.K., A.D.H.), Kenilworth, NJ 07033
9Department of Pharmacology (S.O.), Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany

Tóm tắt

AbstractThe 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.

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Endocrinology

Tập 157 Số 1

176-194

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