{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:34:55Z","timestamp":1790836495220,"version":"4.1.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T00:00:00Z","timestamp":1628121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>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 \u22650.98, n = 5\u20136) from the upper or lower-half of the small intestine in mice or in the lower half in rats. Furthermore, HS014\u2014an often used MC4R antagonist, which we found to be a partial agonist\u2014did 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.<\/jats:p>","DOI":"10.3389\/fendo.2021.690387","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T13:43:28Z","timestamp":1628171008000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["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"],"prefix":"10.3389","volume":"12","author":[{"given":"Rune E.","family":"Kuhre","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida M.","family":"Modvig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara L.","family":"Jepsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00fcs\u00fcn S.","family":"Kizilkaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilie","family":"B\u00e6ch-Laursen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Reimann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona M.","family":"Gribble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette M.","family":"Rosenkilde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens J.","family":"Holst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.03.054","article-title":"Biology of Incretins: GLP-1 and GIP","volume":"132","author":"Baggio","year":"2007","journal-title":"Gastroenterology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00034.2006","article-title":"The Physiology of Glucagon-Like Peptide 1","volume":"87","author":"Holst","year":"2007","journal-title":"Physiol Rev"},{"key":"B3","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.molmet.2019.09.010","article-title":"Glucagon-Like Peptide 1 (GLP-1)","volume":"30","author":"M\u00fcller","year":"2019","journal-title":"Mol Metab"},{"key":"B4","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1586\/17446651.2014.862152","article-title":"Targeting the Intestinal L-Cell for Obesity and Type 2 Diabetes Treatment","volume":"9","author":"Wewer Albrechtsen","year":"2014","journal-title":"Exp Rev Endocrinol Metab"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021115-105439","article-title":"Enteroendocrine Cells: Chemosensors in the Intestinal Epithelium","volume":"78","author":"Gribble","year":"2016","journal-title":"Annu Rev Physiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/en.2011-2170","article-title":"Overlap of Endocrine Hormone Expression in the Mouse Intestine Revealed by Transcriptional Profiling and Flow Cytometry","volume":"153","author":"Habib","year":"2012","journal-title":"Endocrinology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1210\/en.2012-1595","article-title":"A Major Lineage of Enteroendocrine Cells Coexpress CCK, Secretin, GIP, GLP-1, PYY, and Neurotensin But Not Somatostatin","volume":"153","author":"Egerod","year":"2012","journal-title":"Endocrinology"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2337\/db18-0883","article-title":"Comparison of Human and Murine Enteroendocrine Cells by Transcriptomic and Peptidomic Profiling","volume":"68","author":"Roberts","year":"2019","journal-title":"Diabetes"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1210\/en.2014-1710","article-title":"An Analysis of Cosecretion and Coexpression of Gut Hormones From Male Rat Proximal and Distal Small Intestine","volume":"156","author":"Svendsen","year":"2015","journal-title":"Endocrinology"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0598","article-title":"Chronic Treatment With a Melanocortin-4 Receptor Agonist Causes Weight Loss, Reduces Insulin Resistance, and Improves Cardiovascular Function in Diet-Induced Obese Rhesus Macaques","volume":"62","author":"Kievit","year":"2013","journal-title":"Diabetes"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.10.004","article-title":"The Melanocortin-4 Receptor Is Expressed in Enteroendocrine L Cells and Regulates the Release of Peptide YY and Glucagon-Like Peptide 1 In\u00a0Vivo","volume":"20","author":"Panaro","year":"2014","journal-title":"Cell Metab"},{"key":"B12","doi-asserted-by":"publisher","first-page":"100990","DOI":"10.1016\/j.molmet.2020.100990","article-title":"Intestine-Selective Reduction of Gcg Expression Reveals the Importance of the Distal Gut for GLP-1 Secretion","volume":"37","author":"Panaro","year":"2020","journal-title":"Mol Metab"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2021.04.014","article-title":"A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans","author":"Sun","year":"2021","journal-title":"Gastroenterology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-4024","article-title":"RM-493, a Melanocortin-4 Receptor (MC4R) Agonist, Increases Resting Energy Expenditure in Obese Individuals","volume":"100","author":"Chen","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B15","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/S0014-5793(98)01331-3","article-title":"Natural Agonist Enhancing Bis-His Zinc-Site in Transmembrane Segment V of the Tachykinin NK3 Receptor","volume":"439","author":"Rosenkilde","year":"1998","journal-title":"FEBS Lett"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0037","article-title":"The Melanocortin-4 Receptor: Physiology, Pharmacology, and Pathophysiology","volume":"31","author":"Tao","year":"2010","journal-title":"Endocrine Rev"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13384","article-title":"N-Terminally and C-Terminally Truncated Forms of Glucose-Dependent Insulinotropic Polypeptide Are High-Affinity Competitive Antagonists of the Human GIP Receptor","volume":"173","author":"Hansen","year":"2016","journal-title":"Br J Pharmacol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.bcp.2018.01.040","article-title":"Human GIP(3-30)NH2 Inhibits G Protein-Dependent as Well as G Protein-Independent Signaling and is Selective for the GIP Receptor With High-Affinity Binding to Primate But Not Rodent GIP Receptors","volume":"150","author":"Gabe","year":"2018","journal-title":"Biochem Pharmacol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2017.07.014","article-title":"Single-Cell RNA-Sequencing Reveals a Distinct Population of Proglucagon-Expressing Cells Specific to the Mouse Upper Small Intestine","volume":"6","author":"Glass","year":"2017","journal-title":"Mol Metab"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.09.001","article-title":"Single Cell Transcriptomic Profiling of Large Intestinal Enteroendocrine Cells in Mice - Identification of Selective Stimuli for Insulin-Like Peptide-5 and Glucagon-Like Peptide-1 Co-Expressing Cells","volume":"29","author":"Billing","year":"2019","journal-title":"Mol Metab"},{"key":"B21","doi-asserted-by":"publisher","first-page":"107833","DOI":"10.1016\/j.celrep.2020.107833","article-title":"Labeling and Characterization of Human GLP-1-Secreting L-Cells in Primary Ileal Organoid Culture","volume":"31","author":"Goldspink","year":"2020","journal-title":"Cell Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1321","article-title":"Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors","volume":"156","author":"Brighton","year":"2015","journal-title":"Endocrinology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.2337\/diab.43.4.535","article-title":"Tissue and Plasma Concentrations of Amidated and Glycine-Extended Glucagon-Like Peptide I in Humans","volume":"43","author":"Orskov","year":"1994","journal-title":"Diabetes"},{"key":"B24","doi-asserted-by":"publisher","first-page":"00515","DOI":"10.1210\/jc.2019-00515","article-title":"Sacubitril\/valsartan Augments Postprandial Plasma Concentrations of Active GLP-1 When Combined With Sitagliptin in Men","volume":"2019","author":"Wewer Albrechtsen","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-005-2166-x","article-title":"HS014, A Selective Melanocortin-4 (MC4) Receptor Antagonist, Modulates the Behavioral Effects of Morphine in Mice","volume":"180","author":"Ercil","year":"2005","journal-title":"Psychopharmacology"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1998.8389","article-title":"Selective Antagonist for the Melanocortin 4 Receptor (HS014) Increases Food Intake in Free-Feeding Rats","volume":"245","author":"Kask","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12158","article-title":"Systemic Bile Acid Sensing by G Protein-Coupled Bile Acid Receptor 1 (GPBAR1) Promotes PYY and GLP-1 Release","volume":"169","author":"Ullmer","year":"2013","journal-title":"Br J Pharmacol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.molmet.2018.03.007","article-title":"Bile Acids are Important Direct and Indirect Regulators of the Secretion of Appetite- and Metabolism-Regulating Hormones From the Gut and Pancreas","volume":"11","author":"Kuhre","year":"2018","journal-title":"Mol Metab"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1019","article-title":"Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein\u2013Coupled Receptor Ffar2","volume":"61","author":"Tolhurst","year":"2012","journal-title":"Diabetes"},{"key":"B30","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.molmet.2017.11.005","article-title":"Mechanistic Insights Into the Detection of Free Fatty and Bile Acids by Ileal Glucagon-Like Peptide-1 Secreting Cells","volume":"7","author":"Goldspink","year":"2018","journal-title":"Mol Metab"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1210\/en.2016-1334","article-title":"GPR119, a Major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Coacting in Synergy With FFA1 (Gpr40)","volume":"157","author":"Ekberg","year":"2016","journal-title":"Endocrinology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.14814\/phy2.13140","article-title":"Chenodeoxycholic Acid Stimulates Glucagon-Like Peptide-1 Secretion in Patients After Roux-En-Y Gastric Bypass","volume":"5","author":"Nielsen","year":"2017","journal-title":"Physiol Rep"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4420-2","article-title":"Chylomicrons Stimulate Incretin Secretion in Mouse and Human Cells","volume":"60","author":"Psichas","year":"2017","journal-title":"Diabetologia"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1136\/gut.20.8.653","article-title":"Distribution of the Gut Hormones in the Primate Intestinal Tract","volume":"20","author":"Bryant","year":"1979","journal-title":"Gut"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(83)80080-8","article-title":"Endocrine Cells in Human Intestine: An Immunocytochemical Study","volume":"85","author":"Sjolund","year":"1983","journal-title":"Gastroenterology"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.1992.tb01464.x","article-title":"Glucagon-Like Peptide-1 Cells in the Gastrointestinal Tract and Pancreas of Rat, Pig and Man","volume":"22","author":"Eissele","year":"1992","journal-title":"Eur J Clin Invest"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-0115(03)00125-3","article-title":"GLP-1 and GIP are Colocalized in a Subset of Endocrine Cells in the Small Intestine","volume":"114","author":"Mortensen","year":"2003","journal-title":"Regul Peptides"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00326.2004","article-title":"Human Duodenal Enteroendocrine Cells: Source of Both Incretin Peptides, GLP-1 and GIP","volume":"290","author":"Theodorakis","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B39","article-title":"Novel Insight Into the Distribution of L-Cells in the Rat Intestinal Tract","volume":"5","author":"Hansen","year":"2013","journal-title":"Am J Trans Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.soard.2015.02.011","article-title":"Detailed Characterization of Incretin Cell Distribution Along the Human Small Intestine","volume":"11","author":"Guedes","year":"2015","journal-title":"Surg Obes Related Dis"},{"key":"B41","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s13104-016-1872-2","article-title":"The Intestinal Distribution Pattern of Appetite- and Glucose Regulatory Peptides in Mice, Rats and Pigs","volume":"9","author":"Wewer Albrechtsen","year":"2016","journal-title":"BMC Res Notes"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e58533","DOI":"10.3791\/58533","article-title":"Mechanisms Underlying Gut Hormone Secretion Using the Isolated Perfused Rat Small Intestine","author":"Kuhre","year":"2019","journal-title":"JoVE"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.14814\/phy2.13507","article-title":"On the Relationship Between Glucose Absorption and Glucose-Stimulated Secretion of GLP-1, Neurotensin, and PYY From Different Intestinal Segments in the Rat","volume":"5","author":"Kuhre","year":"2017","journal-title":"Physiol Rep"},{"key":"B44","doi-asserted-by":"publisher","first-page":"370","DOI":"10.2337\/db14-0807","article-title":"Molecular Mechanisms of Glucose-Stimulated GLP-1 Secretion From Perfused Rat Small Intestine","volume":"64","author":"Kuhre","year":"2014","journal-title":"Diabetes"},{"key":"B45","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/sj.bjp.0701804","article-title":"Discovery of Novel Melanocortin4 Receptor Selective MSH Analogues","volume":"124","author":"Schi\u00f6th","year":"1998","journal-title":"Br J Pharmacol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2015.09.046","article-title":"A Fragment of the Escherichia Coli ClpB Heat-Shock Protein Is a Micromolar Melanocortin 1 Receptor Agonist","volume":"25","author":"Ericson","year":"2015","journal-title":"Bioorg Med Chem Lett"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijo.0801400","article-title":"Elevated Plasma Levels of Alpha-Melanocyte Stimulating Hormone (Alpha-MSH) Are Correlated With Insulin Resistance in Obese Men","volume":"24","author":"Katsuki","year":"2000","journal-title":"Int J Obes Related Metab Disorders: J Int Assoc Study Obes"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.111.627331","article-title":"Plasma Alpha-Melanocyte Stimulating Hormone Predicts Outcome in Ischemic Stroke","volume":"42","author":"Zierath","year":"2011","journal-title":"Stroke"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/15.8.1212","article-title":"Plasma Concentrations of Alpha-Melanocyte-Stimulating Hormone Are Elevated in Patients on Chronic Haemodialysis","volume":"15","author":"Airaghi","year":"2000","journal-title":"Nephrology Dialysis Transplantation: Off Publ Eur Dialysis Transplant Assoc  Eur Renal Assoc"},{"key":"B50","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.molmet.2018.08.006","article-title":"Quantitative Mass Spectrometry for Human Melanocortin Peptides In Vitro and In Vivo Suggests Prominent Roles for Beta-MSH and Desacetyl Alpha-MSH in Energy Homeostasis","volume":"17","author":"Kirwan","year":"2018","journal-title":"Mol Metab"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.690387\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T13:43:31Z","timestamp":1628171011000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.690387\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,5]]},"references-count":50,"alternative-id":["10.3389\/fendo.2021.690387"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.690387","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,5]]},"article-number":"690387"}}