Neurotensin Regulates Proliferation and Stem Cell Function in the Small Intestine in a Nutrient-Dependent Manner.

Stephanie A Rock,Kai Jiang,Jing Li,Chi Wang,Heidi L Weiss,Yuanyuan Wu,B Mark Evers,Tianyan Gao,Jianhang Jia,Yajuan Liu

doi:10.1016/j.jcmgh.2021.09.006

Stephanie A Rock, Kai Jiang + Show 8 more

Open Access

https://doi.org/10.1016/j.jcmgh.2021.09.006

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Abstract

Background & AimsIntestinal stem cells (ISCs) are sensitive to dietary alterations and nutrient availability. Neurotensin (NT), a gut peptide localized predominantly to the small bowel and released by fat ingestion, stimulates the growth of intestinal mucosa under basal conditions and during periods of nutrient deprivation, suggesting a possible role for NT on ISC function.MethodsLeucine-rich repeat-containing G-protein coupled receptor 5-Enhanced Green Fluorescent Protein (Lgr5-EGFP) NT wild type (Nt+/+) and Lgr5-EGFP NT knockout (Nt-/-) mice were fed ad libitum or fasted for 48 hours. Small intestine tissue and crypts were examined by gene expression analyses, fluorescence-activated cell sorting, Western blot, immunohistochemistry, and crypt-derived organoid culture. Drosophila expressing NT in midgut enteroendocrine cells were fed a standard diet or low-energy diet and esg-green fluorescent protein+ ISCs were quantified via immunofluorescence.ResultsLoss of NT impaired crypt cell proliferation and ISC function in a manner dependent on nutrient status. Under nutrient-rich conditions, NT stimulated extracellular signal-regulated kinases 1 and 2 signaling and the expression of genes that promote cell-cycle progression, leading to crypt cell proliferation. Under conditions of nutrient depletion, NT stimulated WNT/β-catenin signaling and promoted an ISC gene signature, leading to enhanced ISC function. NT was required for the induction of WNT/β-catenin signaling and ISC-specific gene expression during nutrient depletion, and loss of NT reduced crypt cell proliferation and impaired ISC function and Lgr5 expression in the intestine during fasting. Conversely, the expression of NT in midgut enteroendocrine cells of Drosophila prevented loss of ISCs during nutrient depletion.ConclusionsCollectively, our findings establish an evolutionarily conserved role for NT in ISC maintenance during nutritional stress. GSE182828

Highlights

BACKGROUND & AIMSIntestinal stem cells (ISCs) are sensicells that rapidly proliferate within the crypt and terminally tive to dietary alterations and nutrient availability
WNT/b-catenin signaling is an evolutionarily conserved nutrient-rich conditions, NT stimulated ERK1/2 signaling and pathway that plays a critical role in intestinal homeostasis.[8] the expression of genes that promote cell-cycle progression, leading to crypt cell proliferation
Abbreviations used in this paper: AKT, _; cDNA, complementary DNA; NT was required for the induction of WNT/b-catenin signaling

Summary

Introduction

Intestinal stem cells (ISCs) are sensicells that rapidly proliferate within the crypt and terminally tive to dietary alterations and nutrient availability. Neurotensin differentiate as they progress up the crypt–villus axis. (NT), a gut peptide localized predominantly to the small bowel and released by fat ingestion, stimulates the growth of intesti- genitor cells differentiate into either absorptive (enter- nal mucosa under basal conditions and during periods of ocytes) or secretory (goblet, Paneth, enteroendocrine [EE]) nutrient deprivation, suggesting a possible role for NT on ISC cells that perform the primary functions of the intestinal epithelium, including nutrient absorption, digestion, and function. Protection from microbial infections.[1] The process of pro- 89 þ/þ

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