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

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Richards, Paul 
Pais, Ramona 
Habib, Abdella M 
Brighton, Cheryl A 
Yeo, Giles SH 

Abstract

UNLABELLED: 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. METHODS: Transgenic 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. RESULTS: Two 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. CONCLUSION: Mice 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.

Description

Keywords

Enteroendocrine, GLP-1, High fat diet, L-cell, Animals, Cells, Cultured, Diet, High-Fat, Enteroendocrine Cells, Gene Expression, Glucagon-Like Peptide 1, Homeobox Protein Nkx-2.2, Male, Mice, Inbred C57BL, Primary Cell Culture

Journal Title

Peptides

Conference Name

Journal ISSN

0196-9781
1873-5169

Volume Title

77

Publisher

Elsevier BV
Sponsorship
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_UU_12012/3)
Medical Research Council (MC_UU_12012/5/B)
Medical Research Council (MC_PC_12012)
This work was funded by grants from the Wellcome Trust (WT088357/Z/09/Z and WT084210/Z/07/Z), the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/3) and Full4Health (FP7/2011-2015, grant agreement n° 266408). GLP-1 immuno-assays were performed by Keith Burling at the MRC-MDU.