A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Standard

A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans. / Sun, Emily W.; Iepsen, Eva W.; Pezos, Nektaria; Lumsden, Amanda L.; Martin, Alyce M.; Schober, Gudrun; Isaacs, Nichole J.; Rayner, Christopher K.; Nguyen, Nam Q.; de Fontgalland, Dayan; Rabbitt, Philippa; Hollington, Paul; Wattchow, David A.; Hansen, Torben; Holm, Jens Christian; Liou, Alice P.; Jackson, V. Margaret; Torekov, Signe S.; Young, Richard L.; Keating, Damien J.

I: Gastroenterology, Bind 161, Nr. 2, 2021, s. 536-547.e2.

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Harvard

Sun, EW, Iepsen, EW, Pezos, N, Lumsden, AL, Martin, AM, Schober, G, Isaacs, NJ, Rayner, CK, Nguyen, NQ, de Fontgalland, D, Rabbitt, P, Hollington, P, Wattchow, DA, Hansen, T, Holm, JC, Liou, AP, Jackson, VM, Torekov, SS, Young, RL & Keating, DJ 2021, 'A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans', Gastroenterology, bind 161, nr. 2, s. 536-547.e2. https://doi.org/10.1053/j.gastro.2021.04.014

APA

Sun, E. W., Iepsen, E. W., Pezos, N., Lumsden, A. L., Martin, A. M., Schober, G., Isaacs, N. J., Rayner, C. K., Nguyen, N. Q., de Fontgalland, D., Rabbitt, P., Hollington, P., Wattchow, D. A., Hansen, T., Holm, J. C., Liou, A. P., Jackson, V. M., Torekov, S. S., Young, R. L., & Keating, D. J. (2021). A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans. Gastroenterology, 161(2), 536-547.e2. https://doi.org/10.1053/j.gastro.2021.04.014

Vancouver

Sun EW, Iepsen EW, Pezos N, Lumsden AL, Martin AM, Schober G o.a. A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans. Gastroenterology. 2021;161(2):536-547.e2. https://doi.org/10.1053/j.gastro.2021.04.014

Author

Sun, Emily W. ; Iepsen, Eva W. ; Pezos, Nektaria ; Lumsden, Amanda L. ; Martin, Alyce M. ; Schober, Gudrun ; Isaacs, Nichole J. ; Rayner, Christopher K. ; Nguyen, Nam Q. ; de Fontgalland, Dayan ; Rabbitt, Philippa ; Hollington, Paul ; Wattchow, David A. ; Hansen, Torben ; Holm, Jens Christian ; Liou, Alice P. ; Jackson, V. Margaret ; Torekov, Signe S. ; Young, Richard L. ; Keating, Damien J. / A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans. I: Gastroenterology. 2021 ; Bind 161, Nr. 2. s. 536-547.e2.

Bibtex

@article{345a7cfa2f464ad1ba76a2ba28fb5ba1,
title = "A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans",
abstract = "Objective: Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. Design: GLP-1 and PYY levels were assessed in body mass index–matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. Results: Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. Conclusion: Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders.",
keywords = "alpha-MSH, Enteroendocrine, GLP-1, Gut hormones, MC4R, PYY",
author = "Sun, {Emily W.} and Iepsen, {Eva W.} and Nektaria Pezos and Lumsden, {Amanda L.} and Martin, {Alyce M.} and Gudrun Schober and Isaacs, {Nichole J.} and Rayner, {Christopher K.} and Nguyen, {Nam Q.} and {de Fontgalland}, Dayan and Philippa Rabbitt and Paul Hollington and Wattchow, {David A.} and Torben Hansen and Holm, {Jens Christian} and Liou, {Alice P.} and Jackson, {V. Margaret} and Torekov, {Signe S.} and Young, {Richard L.} and Keating, {Damien J.}",
note = "Publisher Copyright: {\textcopyright} 2021",
year = "2021",
doi = "10.1053/j.gastro.2021.04.014",
language = "English",
volume = "161",
pages = "536--547.e2",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "Elsevier",
number = "2",

}

RIS

TY - JOUR

T1 - A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans

AU - Sun, Emily W.

AU - Iepsen, Eva W.

AU - Pezos, Nektaria

AU - Lumsden, Amanda L.

AU - Martin, Alyce M.

AU - Schober, Gudrun

AU - Isaacs, Nichole J.

AU - Rayner, Christopher K.

AU - Nguyen, Nam Q.

AU - de Fontgalland, Dayan

AU - Rabbitt, Philippa

AU - Hollington, Paul

AU - Wattchow, David A.

AU - Hansen, Torben

AU - Holm, Jens Christian

AU - Liou, Alice P.

AU - Jackson, V. Margaret

AU - Torekov, Signe S.

AU - Young, Richard L.

AU - Keating, Damien J.

N1 - Publisher Copyright: © 2021

PY - 2021

Y1 - 2021

N2 - Objective: Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. Design: GLP-1 and PYY levels were assessed in body mass index–matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. Results: Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. Conclusion: Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders.

AB - Objective: Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. Design: GLP-1 and PYY levels were assessed in body mass index–matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. Results: Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. Conclusion: Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders.

KW - alpha-MSH

KW - Enteroendocrine

KW - GLP-1

KW - Gut hormones

KW - MC4R

KW - PYY

U2 - 10.1053/j.gastro.2021.04.014

DO - 10.1053/j.gastro.2021.04.014

M3 - Journal article

C2 - 33848536

AN - SCOPUS:85107380248

VL - 161

SP - 536-547.e2

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -

ID: 279633702