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Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

Journal article
Authors Ara Koh
Antonio Molinaro
Marcus Ståhlman
Muhammad Tanweer Khan
Caroline Schmidt
Louise Mannerås Holm
Hao Wu
Alba Carreras
Louise Olofsson
Per-Olof Bergh
V. Gerdes
A. Hartstra
M. de Brauw
Rosie Perkins
Max Nieuwdorp
Göran Bergström
Fredrik Bäckhed
Published in Cell
Volume 175
Issue 4
Pages 947-+
ISSN 0092-8674
Publication year 2018
Published at Wallenberg Laboratory
Pages 947-+
Language en
Links dx.doi.org/10.1016/j.cell.2018.09.0...
Keywords gut microbiota, receptor substrate-1, serum metabolome, amino-acids, protein, pathway, obesity, activation, autophosphorylation, disease, Biochemistry & Molecular Biology, Cell Biology, iences, v66, p1218, hroder i, 1991, journal of biological chemistry, v266, p13572
Subject categories Cell Biology, Molecular biology

Abstract

Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38 gamma MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes.

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