Neurotensin Is Co-Expressed, Co-Released And Acts Together With Glp-1 And Pyy In Enteroendocrine Control Of Metabolism

Kaare Villum Grunddal; Cecilia F Ratner; Berit Svendsen; Felix Sommer; Maja S Engelstoft; Andreas N Madsen; Jens Pedersen; Mark K Nøhr; Kristoffer L Egerod; Andrea R Nawrocki; Timothy Kowalski; Andrew D Howard; Steen Seier Poulsen; Stefan Offermanns; Gert Fredrik Bäckhed; Jens J Holst; Birgitte Holst; Thue W Schwartz

doi:10.1210/en.2015-1600

Neurotensin Is Co-Expressed, Co-Released And Acts Together With Glp-1 And Pyy In Enteroendocrine Control Of Metabolism

Kaare Villum Grunddal, Cecilia F Ratner, Berit Svendsen, Felix Sommer, Maja S Engelstoft, Andreas N Madsen, Jens Pedersen, Mark K Nøhr, Kristoffer L Egerod, Andrea R Nawrocki, Timothy Kowalski, Andrew D Howard, Steen Seier Poulsen, Stefan Offermanns, Gert Fredrik Bäckhed, Jens J Holst, Birgitte Holst, Thue W Schwartz

86 Citations (Scopus)

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 peptide swereco secreted 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.

Original language	English
Article number	en20151600
Journal	Endocrinology
Volume	157
Issue number	1
Pages (from-to)	176-94
Number of pages	19
ISSN	0013-7227
DOIs	https://doi.org/10.1210/en.2015-1600
Publication status	Published - Jan 2016

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Grunddal, K. V., Ratner, C. F., Svendsen, B., Sommer, F., Engelstoft, M. S., Madsen, A. N., Pedersen, J., Nøhr, M. K., Egerod, K. L., Nawrocki, A. R., Kowalski, T., Howard, A. D., Poulsen, S. S., Offermanns, S., Bäckhed, G. F., Holst, J. J., Holst, B., & Schwartz, T. W. (2016). Neurotensin Is Co-Expressed, Co-Released And Acts Together With Glp-1 And Pyy In Enteroendocrine Control Of Metabolism. Endocrinology, 157(1), 176-94. [en20151600]. https://doi.org/10.1210/en.2015-1600

Grunddal, KV , Ratner, CF, Svendsen, B, Sommer, F, Engelstoft, MS, Madsen, AN, Pedersen, J , Nøhr, MK , Egerod, KL, Nawrocki, AR, Kowalski, T, Howard, AD, Poulsen, SS, Offermanns, S, Bäckhed, GF , Holst, JJ , Holst, B & Schwartz, TW 2016, 'Neurotensin Is Co-Expressed, Co-Released And Acts Together With Glp-1 And Pyy In Enteroendocrine Control Of Metabolism', Endocrinology, vol. 157, no. 1, en20151600, pp. 176-94. https://doi.org/10.1210/en.2015-1600

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title = "Neurotensin Is Co-Expressed, Co-Released And Acts Together With Glp-1 And Pyy In Enteroendocrine Control Of Metabolism",

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 peptide swereco secreted 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.",

author = "Grunddal, {Kaare Villum} and Ratner, {Cecilia F} and Berit Svendsen and Felix Sommer and Engelstoft, {Maja S} and Madsen, {Andreas N} and Jens Pedersen and N{\o}hr, {Mark K} and Egerod, {Kristoffer L} and Nawrocki, {Andrea R} and Timothy Kowalski and Howard, {Andrew D} and Poulsen, {Steen Seier} and Stefan Offermanns and B{\"a}ckhed, {Gert Fredrik} and Holst, {Jens J} and Birgitte Holst and Schwartz, {Thue W}",

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AU - Grunddal, Kaare Villum

AU - Ratner, Cecilia F

AU - Svendsen, Berit

AU - Sommer, Felix

AU - Engelstoft, Maja S

AU - Madsen, Andreas N

AU - Pedersen, Jens

AU - Nøhr, Mark K

AU - Egerod, Kristoffer L

AU - Nawrocki, Andrea R

AU - Kowalski, Timothy

AU - Howard, Andrew D

AU - Poulsen, Steen Seier

AU - Offermanns, Stefan

AU - Bäckhed, Gert Fredrik

AU - Holst, Jens J

AU - Holst, Birgitte

AU - Schwartz, Thue W

PY - 2016/1

Y1 - 2016/1

N2 - 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 peptide swereco secreted 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.

AB - 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 peptide swereco secreted 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.

U2 - 10.1210/en.2015-1600

DO - 10.1210/en.2015-1600

M3 - Journal article

C2 - 26469136

SN - 0013-7227

VL - 157

SP - 176

EP - 194

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 1

M1 - en20151600

ER -

Neurotensin Is Co-Expressed, Co-Released And Acts Together With Glp-1 And Pyy In Enteroendocrine Control Of Metabolism

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