Diet-induced Alteration of Intestinal Stem Cell Function Underlies Obesity and Prediabetes in Mice

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2021 Sep 23

PMID 34552271

Citations 36

Authors

Alexandra Aliluev

Sophie Tritschler

Michael Sterr

Lena Oppenlander

Julia Hinterdobler

Tobias Greisle

Martin Irmler

Johannes Beckers

Na Sun

Axel Walch

Kerstin Stemmer

Alida Kindt

Jan Krumsiek

Matthias H Tschop

Malte D Luecken

Fabian J Theis

Heiko Lickert

Anika Bottcher

Affiliations

Soon will be listed here.

Abstract

Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr-Igf1r-Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.

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