期刊
FRONTIERS IN ENDOCRINOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fendo.2021.690387
关键词
alpha-MSH; melanocortin; melanocortin-4-receptor; glucagon-like peptide-1 secretion; L-cells
资金
- Lundbeck foundation (Lundbeckfonden) [R264-2017-3492, R289-2018-1026]
- Weimann Foundation (Kobmand i Odense Johann og Hanne Weimann fodt Seed fonden)
- Novo Nordisk Center for Basic Metabolic Research (Novo Nordisk Foundation, Denmark)
- Novo Nordisk grant [NNF15OC0016574]
- European Research Council under the European Union's Horizon 2020 research and innovation program [695069]
- Independent Research Fund Denmark (Danmarks Frie Forskningsfond) [0129-00002B]
- Wellcome Trust [106262/Z/14/Z, 106263/Z/14/Z]
- UK Medical Research Council [MRC_MC_UU_12012/3]
- Valter Alex Torbjorn Eichmuller [VAT Eichmuller-2020-117043]
- Kirsten and Freddy Johansen's Foundation [KFJ-2017-112697]
Studies have shown low expression of MC4R in L-cells of mice and humans, and administration of MC4R agonists did not stimulate GLP-1 secretion in isolated perfused mouse and rat small intestine models. The data suggest that MC4R-activated GLP-1 secretion in rodents may occur exclusively in the colon or involve extra-intestinal signaling.
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.
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