1. A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans.
- Author
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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, and Keating DJ
- Subjects
- Autocrine Communication, Blood Glucose metabolism, Case-Control Studies, Enteroendocrine Cells drug effects, Glucose administration & dosage, Glucose Tolerance Test, Humans, Intestinal Mucosa drug effects, Loss of Function Mutation, Paracrine Communication, Pro-Opiomelanocortin genetics, Receptor, Melanocortin, Type 4 agonists, Receptor, Melanocortin, Type 4 genetics, Secretory Pathway, Signal Transduction, Time Factors, alpha-MSH pharmacology, Enteroendocrine Cells metabolism, Glucagon-Like Peptide 1 metabolism, Intestinal Mucosa metabolism, Peptide YY metabolism, Pro-Opiomelanocortin metabolism, Receptor, Melanocortin, Type 4 metabolism, alpha-MSH metabolism
- 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., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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