High fat diet impairs the function of glucagon-like peptide-1 producing L-cells

Richards, Pamela Spence; Pais, Ramona; Habib, Abdella M.; Brighton, Cheryl A.; Yeo, Giles S.H.; Reimann, Frank; Gribble, Fiona M.

doi:10.1016/j.peptides.2015.06.006

Cited by 111 publications

(90 citation statements)

References 19 publications

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“…Our results further support the idea of the plasticity of the intestinal endocrine system (43). Although it remains undetermined which stages of EEC differentiation (stem cells, progenitor cells, or differentiated cells) are affected by the luminal environment, in the cecum the changes in peptide pattern expression were associated with an increase in Neurod1 and Pax6 but not in Neurog3 and Math1 expression.…”

Section: Discussionsupporting

confidence: 87%

Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism

et al. 2019

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Current fructose consumption levels often overwhelm the intestinal capacity to absorb fructose. We investigated the impact of fructose malabsorption on intestinal endocrine function and addressed the role of the microbiota in this process. To answer this question, a mouse model of moderate fructose malabsorption [ketohexokinase mutant (KHK)−/−] and wild‐type (WT) littermate mice were used and received a 20%‐fructose (KHK‐F and WT‐F) or 20%‐glucose diet. Cholecystokinin (Cck) mRNA and protein expression in the ileum and cecum, as well as preproglucagon (Gcg) and neurotensin (Nts) mRNA expression in the cecum, increased in KHK‐F mice. In KHK‐F mice, triple‐label immunohistochemistry showed major up‐regulation of CCK in enteroendocrine cells (EECs) that were glucagon‐like peptide‐1 (GLP‐1)+/Peptide YY (PYY−) in the ileum and colon and GLP‐1−/PYY− in the cecum. The cecal microbiota composition was drastically modified in the KHK‐F in association with an increase in glucose, propionate, succinate, and lactate concentrations. Antibiotic treatment abolished fructose malabsorption‐dependent induction of cecal Cck mRNA expression and, in mouse GLUTag and human NCI‐H716 cells, Cck mRNA expression levels increased in response to propionate, both suggesting a microbiota‐dependent process. Fructose reaching the lower intestine can modify the composition and metabolism of the microbiota, thereby stimulating the production of CCK from the EECs possibly in response to propionate.—Zhang, X., Grosfeld, A., Williams, E., Vasiliauskas, D., Barretto, S., Smith, L., Mariadassou, M., Philippe, C., Devime, F., Melchior, C., Gourcerol, G., Dourmap, N., Lapaque, N., Larraufie, P., Blottière, H. M., Herberden, C., Gerard, P., Rehfeld, J. F., Ferraris, R. P., Fritton, J. C., Ellero‐Simatos, S., Douard, V. Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism. FASEB J. 33, 7126–7142 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 87%

Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism

et al. 2019

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“…There could be a link between these effects, as illustrated for instance in a study performed in obese prebiotic-fed mice which reported that the gut microbiota influenced the release of substrates of DPP-4 such as GLP-1 and GLP-2 [36]. Furthermore, a high-fat diet can impair enteroendocrine cell function and the release of GLP-1, as confirmed here [37]. We propose that the increase in active GLP-1 in mice treated with vildagliptin can also be partly explained by the increases in propionate in the caecal content [38].…”

Section: Discussionsupporting

confidence: 53%

The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice

et al. 2018

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Aims/hypothesisDipeptidyl peptidase 4 (DPP-4) inhibitors are agents designed to increase the half-life of incretins. Although they are administered orally, little is known about their effects on the gut microbiota and functions, despite the fact that some bacteria present in the gut microbiota exhibit DPP-4-like activity. Our objective was to study the impact of the DPP-4 inhibitor vildagliptin on gut functions and the intestinal ecosystem in a murine model of obesity induced by a Western diet (WD).MethodsTwenty seven male C57BL/6J mice were randomised to receive a control diet, a WD (45% kJ from fat and 17% kJ from sucrose) or a WD + vildagliptin (0.6 mg/ml in drinking water) for 8 weeks.ResultsVildagliptin significantly reduced DPP-4 activity in the caecal content and faeces. Vildagliptin impacted on the composition of the gut microbiota and its metabolic activity. It mainly decreased Oscillibacter spp. (a direct effect independent of DPP-4 activity was shown on cultured O. valericigenes), increased Lactobacillus spp. and propionate, and reduced the ligands of Toll-like receptors 2 and 4. Vildagliptin protected against the reductions in crypt depth and ileal expression of antimicrobial peptides induced by the WD. In the liver, the expression of immune cell populations (Cd3g and Cd11c [also known as Itgax]) and cytokines was decreased in the WD + vildagliptin-fed mice compared with the WD-fed group. Ex vivo exposure of precision-cut liver slices to vildagliptin showed that this response was not related to a direct effect of the drug on the liver tissue.Conclusions/interpretationOur study is the first to consider the DPP-4-like activity of the gut microbiota as a target of DPP-4 inhibition. We propose that vildagliptin exerts beneficial effects at the intestinal level in association with modulation of gut microbiota, with consequences for hepatic immunity. If relevant in humans, this could open new therapeutic uses of DPP-4 inhibition to tackle gut dysfunctions in different pathophysiological contexts.Data availabilityThe sequences used for analysis can be found in the MG-RAST database under the project name MYNEWGUT3.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4647-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…Whereas fats acutely stimulate GLP-1 secretion as evidenced from above, chronic high-fat feeding in mice reduced numbers of GLP-1 and GIP positive cells and significantly decreased the expression of enteroendocrine hormones, nutrient sensing machinery and enteroendocrine-specific transcription factors [Richards et al 2015]. Hayashi and colleagues demonstrated that endoplasmic reticulum stress, induced with excessive doses of palmitate, increased the expression of endoplasmic reticulum stress markers, Chop and BiP, reduced protein levels and function of prohormone convertase 1/3, and decreased GLP-1 secretion from GLUTag cells [Hayashi et al 2014].…”

Section: Fat Sensingmentioning

confidence: 77%

“…Brighton and colleagues measured GLP-1 release from murine ileum mounted in small volume Ussing chambers; they showed that basolateral taurodeoxycholate (TDCA) or a TGR5 agonist stimulated GLP-1 secretion but that the effects of apically-applied TDCA were abolished by inhibition of bile acid uptake across the epithelium. Preferential stimulation of GLP-1 release by basolateral versus apical bile acids was confirmed in the perfused rat gut, leading to the conclusion that bile acid triggered GLP-1 secretion is predominantly mediated by basolaterally located TGR5 on the L cell [Brighton et al 2015]. These findings dampen the hope of developing TGR5 agonists as GLP-1 secretagogues, as TGR5 ligands entering the systemic circulation have been found to trigger gall bladder overfilling [Li et al 2011].…”

Section: Bile Acidsmentioning

confidence: 92%

Stimulation of incretin secreting cells

Reimann¹

2015

EJEA

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High fat diet impairs the function of glucagon-like peptide-1 producing L-cells

Abstract: HighlightsLong term dietary changes impair function of the gut endocrine system.High fat diet impairs nutrient-triggered GLP-1 release from murine small intestine.L-cells from HFD-fed mice have reduced expression of many L-cell-specific genes.

Cited by 111 publications

References 19 publications

Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism

Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism

The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice

Stimulation of incretin secreting cells

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