L-Cell Expression of Melanocortin-4-Receptor Is Marginal in Most of the Small Intestine in Mice and Humans and Direct Stimulation of Small Intestinal Melanocortin-4-Receptors in Mice and Rats Does Not Affect GLP-1 Secretion.

Kuhre RE, Modvig IM, Jepsen SL, Kizilkaya HS, Bæch-Laursen C, Smith CA, Reimann F, Gribble FM, Rosenkilde MM, Holst JJ

Frontiers in endocrinology5 Aug 2021Cited by 4 (Europe PMC)

PMID34421821PMCIDPMC8375664DOI10.3389/fendo.2021.690387PepBankPUB-34421821

Summary

The molecular sensors underlying nutrient-stimulated GLP-1 secretion are currently being investigated. Peripheral administration of melanocortin-4 receptor (MC4R) agonists have been reported to increase GLP-1 plasma concentrations in mice and humans but it is unknown whether this effect results from a direct effect on the GLP-1 secreting L-cells in the intestine, from other effects in the intestine or from extra-intestinal effects. We investigated L-cell expression of MC4R in mouse and human L-cells by reanalyzing publicly available RNA sequencing databases (mouse and human) and by RT-qPCR (mouse), and assessed whether administration of MC4R agonists to a physiologically relevant gut model, isolated perfused mouse and rat small intestine, would stimulate GLP-1 secretion or potentiate glucose-stimulated secretion. L-cell MC4R expression was low in mouse duodenum and hardly detectable in the ileum and MC4R expression was hardly detectable in human L-cells. In isolated perfused mouse and rat intestine, neither intra-luminal nor intra-arterial administration of NDP-alpha-MSH, a potent MC4R agonist, had any effect on GLP-1 secretion (P ≥0.98, n = 5-6) from the upper or lower-half of the small intestine in mice or in the lower half in rats. Furthermore, HS014-an often used MC4R antagonist, which we found to be a partial agonist-did not affect the glucose-induced GLP-1 response in the rat, P = 0.62, n = 6). Studies on transfected COS7-cells confirmed bioactivity of the used compounds and that concentrations employed were well within in the effective range. Our combined data therefore suggest that MC4R-activated GLP-1 secretion in rodents either exclusively occurs in the colon or involves extra-intestinal signaling.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study3

1 result from studies that gave the peptide. No result from this study comes from people.

01LabEx vivo tissueEfficacy outcome
In isolated perfused mouse and rat small intestine, neither intra-luminal nor intra-arterial NDP-alpha-MSH had any effect on GLP-1 secretion.
In plain wordsIn lab tests on isolated mouse and rat intestine, NDP-alpha-MSH did not change GLP-1 release.
Peptide
Melanotan I (afamelanotide)
Outcome
No significant changeGLP-1 secretion from perfused small intestine
Study
mouse and ratn: not reported in source
isolated perfused small intestine
Outcome group
Hormone levels · Endocrine and hormones
Studied dose
Dose not stated · intra-luminal or intra-arterialAs given in this study (mouse and rat).
Source sentences
Summary
In isolated perfused mouse and rat intestine, neither intra-luminal nor intra-arterial administration of NDP-alpha-MSH, a potent MC4R agonist, had any effect on GLP-1 secretion (P ≥0.98, n = 5-6) from the upper or lower-half of the small intestine in mice or in the lower half in rats.
1 context sentence(design, population, supporting numbers)
Summary · context
We investigated L-cell expression of MC4R in mouse and human L-cells by reanalyzing publicly available RNA sequencing databases (mouse and human) and by RT-qPCR (mouse), and assessed whether administration of MC4R agonists to a physiologically relevant gut model, isolated perfused mouse and rat small intestine, would stimulate GLP-1 secretion or potentiate glucose-stimulated secretion.
Show in the study text Report a problemFND-3442182101

Studies that did not test the peptide alone2

In this study, Melanotan I (afamelanotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Melanotan I (afamelanotide).

02LabNot a test of Melanotan I (afamelanotide) aloneIn vitro (cells)Activity measurement
In transfected COS7 cells, the compounds used were bioactive, with employed concentrations well within the effective range.
In plain wordsIn cells, the compounds used in the study were active at the concentrations employed.
Peptide
Melanotan I (afamelanotide)
Outcome
Not applicableBioactivity of the compounds in COS7 cells
Study
n: not reported in source
transfected COS7 cells
Outcome group
Receptor activity and mechanism · Pharmacology
Source sentences
Summary
Studies on transfected COS7-cells confirmed bioactivity of the used compounds and that concentrations employed were well within in the effective range.
1 context sentence(design, population, supporting numbers)
Summary · context
We investigated L-cell expression of MC4R in mouse and human L-cells by reanalyzing publicly available RNA sequencing databases (mouse and human) and by RT-qPCR (mouse), and assessed whether administration of MC4R agonists to a physiologically relevant gut model, isolated perfused mouse and rat small intestine, would stimulate GLP-1 secretion or potentiate glucose-stimulated secretion.
In this study, Melanotan I (afamelanotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Melanotan I (afamelanotide).
Show in the study text Report a problemFND-3442182103
03LabNot a test of Melanotan I (afamelanotide) aloneOther designMechanism
L-cell MC4R expression was low in mouse duodenum and hardly detectable in mouse ileum, and hardly detectable in human L-cells.
In plain wordsIn lab analyses, the MC4R receptor was found at very low levels in mouse and human gut L-cells.
Peptide
Melanotan I (afamelanotide)
Outcome
Not applicableL-cell MC4R expression
Study
mouse and humann: not reported in source
RNA sequencing databases and RT-qPCR
Outcome group
Receptor activity and mechanism · Endocrine and hormones
Source sentences
Summary
L-cell MC4R expression was low in mouse duodenum and hardly detectable in the ileum and MC4R expression was hardly detectable in human L-cells.
1 context sentence(design, population, supporting numbers)
Summary · context
We investigated L-cell expression of MC4R in mouse and human L-cells by reanalyzing publicly available RNA sequencing databases (mouse and human) and by RT-qPCR (mouse), and assessed whether administration of MC4R agonists to a physiologically relevant gut model, isolated perfused mouse and rat small intestine, would stimulate GLP-1 secretion or potentiate glucose-stimulated secretion.
In this study, Melanotan I (afamelanotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Melanotan I (afamelanotide).
Show in the study text Report a problemFND-3442182102

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
13 Oct 2026, 21:44 UTC
Study results updated
Version 1
13 Oct 2026, 16:31 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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