A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans

Sun, Emily; Iepsen, Eva Winning; Pezos, Nektaria; Lumsden, Amanda L.; Martin, Alyce M.; Schober, Gudrun; Isaacs, Nichole J.; Rayner, Christopher K.; Nguyen, Nam Q.; Fontgalland, Dayan de; Rabbitt, Philippa; Hollington, Paul; Wattchow, David; Hansen, Torben; Holm, Jens-Christian; Liou, Alice P.; Jackson, V. Margaret; Torekov, Signe S.; Young, Richard L.; Keating, Damien J.

doi:10.1053/j.gastro.2021.04.014

Cited by 10 publications

(7 citation statements)

References 61 publications

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“…Because α7nAChR might be expressed on intermediary intestinal cell types that release paracrine factors (e.g. α‐MSH) important to GLP‐1 secretion, 20 indirect actions of GTS‐21 mediated by these factors must also be taken into account. Intriguingly, it is now understood that islet alpha cells secrete not only glucagon, but also GLP‐1 under conditions of stress, as might occur in db/db mice 21 .…”

Section: Discussionmentioning

confidence: 99%

The alpha‐7 nicotinic acetylcholine receptor agonist GTS‐21 engages the glucagon‐like peptide‐1 incretin hormone axis to lower levels of blood glucose in db/db mice

Meng

Chepurny

Leech

et al. 2022

Diabetes Obesity Metabolism

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Aim: To establish if alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively.Materials and Methods: Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, peptide tyrosine tyrosine 1-36 (PYY1-36), glucose-dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA. A GLP-1R-mediated action of GTS-21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP-1R knockout (KO) mice, or by coadministration of GTS-21 with the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the GLP-1R antagonist, exendin (9-39). Insulin sensitivity was assessed in an insulin tolerance test.Results: Single or multiple dose GTS-21 (0.5-8.0 mg/kg) acted in a dose-dependent manner to lower levels of blood glucose in the OGTT using 10-14 week-old male and female db/db mice. This action of GTS-21 was reproduced by the α7nAChR agonist, PNU-282987, was enhanced by sitagliptin, was counteracted by exendin (9-39), and was absent in α7nAChR and GLP-1R KO mice. Plasma GLP-1, PYY1-36, GIP, glucagon, and insulin levels increased in response to GTS-21, but insulin sensitivity, body weight, and food intake were unchanged.Conclusions: α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent to coordinate α7nAChR and GLP-1R stimulation. Thus α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

The alpha‐7 nicotinic acetylcholine receptor agonist GTS‐21 engages the glucagon‐like peptide‐1 incretin hormone axis to lower levels of blood glucose in db/db mice

Meng

Chepurny

Leech

et al. 2022

Diabetes Obesity Metabolism

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“…It is possible that the Mc4r expression, being somewhat lower than Gpr119 and Gpbar1 expression, is insufficient to elicit a secretory response. Given that colonic L-cell Mc4r expression is at similar relatively low levels as observed in duodenal L-cells it seems thus unlikely that direct stimulation of colonic L-cells alone is underlying in vivo GLP-1 responses to MC4R-agonists, although GLP-1 and PYY secretion from ex vivo incubated human colonic mucosal specimens was reported to increase in response to MC4R agonists (13). Modulation by extra-intestinal MC4R not present in the preparation is a possibility that should be addressed in future research, especially, given the apparent absence of MC4R expression in human L-cells.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, they showed that the increase requires gcg expression in the ileum and colon (12), pointing towards that these sites of the intestine are responsible for the increased plasma concentrations. Moreover, it has been shown that humans with natural occurring loss-of-function mutations in MC4R exhibit reduced plasma PYY levels (marker of L-cell secretion from the distal intestine) in response to an OGTT, and GLP-1 and PYY secretion from human gut specimens (obtained from duodenum, ileum and colon) increased in response to incubation with the MC4R agonists MK-0493, LY2112688, a-MSH and NDP-a-MSH (13).…”

Section: Introductionmentioning

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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“…110 A combination of liraglutide therapy and exercise improves maintenance of weight loss (as weight regain after a weight loss is a common problem) compared to either exercise or drug treatment alone. 111 Sun et al 112 have proposed a gutintrinsic melanocortin signalling complex involving α-MSH release and MC4R activation on L cells secretion in humans. This could directly target mucosal MC4R to treat human metabolic disorders including obesity.…”

Section: Nonpeptide Ligandsmentioning

confidence: 99%

Melanocortin‐4 receptor complexity in energy homeostasis,obesity and drug development strategies

Fatima

Ahmed

Fakhro

et al. 2022

Diabetes Obesity Metabolism

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The melanocortin‐4 receptor (MC4R) has been critically investigated for the past two decades, and novel findings regarding MC4R signalling and its potential exploitation in weight loss therapy have lately been emphasized. An association between MC4R and obesity is well established, with disease‐causing mutations affecting 1% to 6% of obese patients. More than 200 MC4R variants have been reported, although conflicting results as to their effects have been found in different cohorts. Most notably, some MC4R gain‐of‐function variants seem to rescue obesity and related complications via specific pathways such as beta‐arrestin (ß‐arrestin) recruitment. Broadly speaking, however, dysfunctional MC4R dysregulates satiety and induces hyperphagia. The picture at the mechanistic level is complicated as, in addition to the canonical G stimulatory pathway, the ß‐arrestin signalling pathway and ions (particularly calcium) seem to interact with MC4R signalling to contribute to or alleviate obesity pathogenesis. Thus, the overall complexity of the MC4R signalling spectra has broadened considerably, indicating there is great potential for the development of new drugs to manage obesity and its related complications. Alpha‐melanocyte‐stimulating hormone is the major endogenous MC4R agonist, but structure‐based ligand discovery studies have identified possible superior and selective agonists that can improve MC4R function. However, some of these agonists characterized in vitro and in vivo confer adverse effects in patients, as demonstrated in clinical trials. In this review, we provide a comprehensive insight into the genetics, function and regulation of MC4R and its contribution to obesity. We also outline new approaches in drug development and emerging drug candidates to treat obesity.

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A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans

Cited by 10 publications

References 61 publications

The alpha‐7 nicotinic acetylcholine receptor agonist GTS‐21 engages the glucagon‐like peptide‐1 incretin hormone axis to lower levels of blood glucose in db/db mice

The alpha‐7 nicotinic acetylcholine receptor agonist GTS‐21 engages the glucagon‐like peptide‐1 incretin hormone axis to lower levels of blood glucose in db/db mice

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

Melanocortin‐4 receptor complexity in energy homeostasis,obesity and drug development strategies

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