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

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

doi:10.1016/j.peptides.2015.06.006

Paul Richards, Ramona Pais + Show 5 more

Open Access

https://doi.org/10.1016/j.peptides.2015.06.006

Copy DOI

Journal: Peptides	Publication Date: Jul 3, 2015
Citations: 105	License type: cc-by

Affiliation: MRC Metabolic Diseases Unit

Abstract

Glucagon-like peptide-1 (GLP-1) acts as a satiety signal and enhances insulin release. This study examined how GLP-1 production from intestinal L-cells is modified by dietary changes. MethodsTransgenic mouse models were utilized in which L-cells could be purified by cell specific expression of a yellow fluorescent protein, Venus. Mice were fed on chow or 60% high fat diet (HFD) for 2 or 16 weeks. L-cells were purified by flow cytometry and analysed by microarray and quantitative RT-PCR. Enteroendocrine cell populations were examined by FACS analysis, and GLP-1 secretion was assessed in primary intestinal cultures. ResultsTwo weeks HFD reduced the numbers of GLP-1 positive cells in the colon, and of GIP positive cells in the small intestine. Purified small intestinal L-cells showed major shifts in their gene expression profiles. In mice on HFD for 16 weeks, significant reductions were observed in the expression of L-cell specific genes, including those encoding gut hormones (Gip, Cck, Sct, Nts), prohormone processing enzymes (Pcsk1, Cpe), granins (Chgb, Scg2), nutrient sensing machinery (Slc5a1, Slc15a1, Abcc8, Gpr120) and enteroendocrine-specific transcription factors (Etv1, Isl1, Mlxipl, Nkx2.2 and Rfx6). A corresponding reduction in the GLP-1 secretory responsiveness to nutrient stimuli was observed in primary small intestinal cultures. ConclusionMice fed on HFD exhibited reduced expression in L-cells of many L-cell specific genes, suggesting an impairment of enteroendocrine cell function. Our results suggest that a western style diet may detrimentally affect the secretion of gut hormones and normal post-prandial signaling, which could impact on insulin secretion and satiety.

Highlights

Hormones from the gut control food intake and insulin release as well as intestinal motility and secretion [1]
To evaluate the frequency of L-cells and their individual production of peptide hormones, we performed FACS analysis of cell suspensions from transgenic mice expressing a yellow fluorescent protein Venus driven by the gcg promoter, which were immunostained for different gut hormones
In large intestinal cell suspensions co-stained with antibodies against CCK and PYY, we observed a particular reduction in the number of L-cells staining strongly for CCK, and a corresponding increase in the intensity of L-cell PYY staining in mice fed on high fat diet (HFD) for 2 weeks (Fig. 2B–D)

Summary

Introduction

Hormones from the gut control food intake and insulin release as well as intestinal motility and secretion [1]. As dietary habits have changed and people consume more fat and sugar, this raises concerns about whether dietary intake affects the release of gut hormones, and whether this in turn might contribute to rising levels of obesity and diabetes. GLP-1, like other gut hormones, is released from enteroendocrine cells (EECs) located in the intestinal epithelium. EECs have a life span of only about 5 days, and are constantly replenished from stem cells in the intestinal crypts. Depending on their position along the gastrointestinal tract, EECs exhibit characteristic hormonal signatures. If it were possible to increase L-cell number, this could lead to increased GLP-1 release and improved glucose tolerance and satiety

Methods

Results

Conclusion