Article ; Online: A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans.
2021 Volume 161, Issue 2, Page(s) 536–547.e2
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 ... ...
| 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. |
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| MeSH term(s) | Autocrine Communication ; Blood Glucose/metabolism ; Case-Control Studies ; Enteroendocrine Cells/drug effects ; Enteroendocrine Cells/metabolism ; Glucagon-Like Peptide 1/metabolism ; Glucose/administration & dosage ; Glucose Tolerance Test ; Humans ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/metabolism ; Loss of Function Mutation ; Paracrine Communication ; Peptide YY/metabolism ; Pro-Opiomelanocortin/genetics ; Pro-Opiomelanocortin/metabolism ; Receptor, Melanocortin, Type 4/agonists ; Receptor, Melanocortin, Type 4/genetics ; Receptor, Melanocortin, Type 4/metabolism ; Secretory Pathway ; Signal Transduction ; Time Factors ; alpha-MSH/metabolism ; alpha-MSH/pharmacology | ||||||||||
| Chemical Substances | Blood Glucose ; MC4R protein, human ; Receptor, Melanocortin, Type 4 ; Peptide YY (106388-42-5) ; alpha-MSH (581-05-5) ; Pro-Opiomelanocortin (66796-54-1) ; Glucagon-Like Peptide 1 (89750-14-1) ; Glucose (IY9XDZ35W2) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2021-04-20 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 80112-4 | ||||||||||
| ISSN | 1528-0012 ; 0016-5085 | ||||||||||
| ISSN (online) | 1528-0012 | ||||||||||
| ISSN | 0016-5085 | ||||||||||
| DOI | 10.1053/j.gastro.2021.04.014 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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