Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion

Panaro, Brandon L.; Yusta, Bernardo; Matthews, Dianne; Koehler, Jacqueline A.; Song, Youngmi; Sandoval, Darleen A.; Drucker, Daniel J.

doi:10.1016/j.molmet.2020.100990

Cited by 42 publications

(41 citation statements)

References 38 publications

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“…To investigate whether any effects of systemic MC4R agonist administration on plasma GLP-1 concentrations in mice ( 11 , 12 ) and humans ( 14 ) may result from direct MC4R-activation at the level of the L-cell, we investigated MC4R expression in mouse and human L-cells by reanalyzing raw data from both bulk RNA sequencing (mouse and human) and single cell RNA sequencing (mouse) ( 8 , 19 – 21 ) as well as by qPCR (mouse). In mice, MC4R was expressed at higher levels than the other melanocortin receptor isoforms and, as previously reported, was enriched in L-cells relative to the surrounding epithelium ( Figure 2A , left panel), which is predominantly constituted from absorptive enterocytes.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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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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Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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“…Most ingested nutrients are absorbed within the proximal small intestine and compared with the distal gut, the upper small intestine receives more vagal afferent innervation, which forms part of a neural circuit that mediates satiety [ 25 , 26 ]. The physiological roles of nutrient-sensing mechanisms in EECs of the distal gut remain elusive, although colonic EECs may respond to locally produced microbial products [ 27 ] and lipid metabolites [ 28 ] and provide signals reflective of long-term dietary history. However, the beneficial metabolic effects of increased nutrient exposure and recruitment of distal EECs following bariatric surgery suggest these mechanisms may be exploited for effective weight and blood glucose control.…”

Section: Enteroendocrine Cells That Release Glp-1 and Gipmentioning

confidence: 99%

“…Nevertheless, GPR119 seems to be an important sensor of ingested fat, as there was reduced GIP secretion following an oral triglyceride challenge in Gpr119 knock-out animals, [ 234 ], and impaired oil-triggered GLP-1 release in mice lacking Gpr119 in L-cells [ 252 ]. The GLP-1 response to GPR119 agonism is more prominent in the distal gut, as it was impaired in mice lacking L-cells in the terminal ileum and large intestine [ 28 ]. Mirroring this finding, GPR119 agonists were more effective at triggering GLP-1 release in vitro from murine colonic than small intestinal cultures, and elevated cAMP in ∼70% of colonic L-cells but only 50% of small intestinal L-cells [ 252 ].…”

Section: Cellular Mechanisms Of Nutrient-induced Gut Hormone Secrementioning

confidence: 99%

“…GLP-1 is produced in large quantities in the distal small intestine and colon, regions of the intestine not typically reached by ingested nutrients, where its release may follow different regulatory mechanisms including control by metabolites of gut microbiota and neurohormonal pathways. Recent studies identified the possible importance of distal L-cells in mediating responses to lipid-derivatives, melanocortin receptor 4 agonists and lipopolysaccharides [ 28 ]. Another question is whether therapeutic activation of GPCRs in EECs could trigger sufficient gut hormone release to produce significant metabolic benefits or satiation.…”

Section: Future Directionsmentioning

confidence: 99%

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Nutrient-Induced Cellular Mechanisms of Gut Hormone Secretion

Gribble

Reimann

2021

Nutrients

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The gastrointestinal tract can assess the nutrient composition of ingested food. The nutrient-sensing mechanisms in specialised epithelial cells lining the gastrointestinal tract, the enteroendocrine cells, trigger the release of gut hormones that provide important local and central feedback signals to regulate nutrient utilisation and feeding behaviour. The evidence for nutrient-stimulated secretion of two of the most studied gut hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), along with the known cellular mechanisms in enteroendocrine cells recruited by nutrients, will be the focus of this review. The mechanisms involved range from electrogenic transporters, ion channel modulation and nutrient-activated G-protein coupled receptors that converge on the release machinery controlling hormone secretion. Elucidation of these mechanisms will provide much needed insight into postprandial physiology and identify tractable dietary approaches to potentially manage nutrition and satiety by altering the secreted gut hormone profile.

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“…115 Exogenous LPS administration promotes GLP-1 secretion in both mice 116 and humans, 83 likely from the distal gut. 117 In fact, administration of LPS abrogates intestinal barrier integrity that makes L cells accessible to LPS thus promoting GLP-1 secretion in Toll-like receptor 4 (TLR4)-dependent mechanism. 83 LPS-induced GLP-1 might function to cope with glucose surge, as seen in inflammatory state, 118 or maintain gut homeostasis following intestinal injury (Figure 2).…”

Section: Lipopolysaccharidementioning

confidence: 99%