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Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

Koh, Ara ; Molinaro, Antonio ; Ståhlman, Marcus ; Khan, Muhammad Tanweer ; Schmidt, Caroline ; Mannerås-Holm, Louise ; Wu, Hao ; Carreras, Alba ; Jeong, Heeyoon ; Olofsson, Louise E. ; Bergh, Per-Olof ; Gerdes, Victor ; Hartstra, Annick ; de Brauw, Maurits ; Perkins, Rosie ; Nieuwdorp, Max ; Bergström, Göran ; Bäckhed, Fredrik

Cell, 2018-11, Vol.175 (4), p.947-961.e17 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1
Autor: Koh, Ara ; Molinaro, Antonio ; Ståhlman, Marcus ; Khan, Muhammad Tanweer ; Schmidt, Caroline ; Mannerås-Holm, Louise ; Wu, Hao ; Carreras, Alba ; Jeong, Heeyoon ; Olofsson, Louise E. ; Bergh, Per-Olof ; Gerdes, Victor ; Hartstra, Annick ; de Brauw, Maurits ; Perkins, Rosie ; Nieuwdorp, Max ; Bergström, Göran ; Bäckhed, Fredrik
Assuntos: 1991 ; activation ; amino-acids ; autophosphorylation ; Biochemistry & Molecular Biology ; Biochemistry and Molecular Biology ; Biokemi och molekylärbiologi ; Cell Biology ; Cellbiologi ; disease ; gut microbiota ; histidine ; hroder i ; iences ; imidazole propionate ; IRS ; journal of biological chemistry ; microbiome ; mTORC1 ; obesity ; p1218 ; p13572 ; p38γ ; p62 ; pathway ; protein ; receptor substrate-1 ; serum metabolome ; v266 ; v66
É parte de: Cell, 2018-11, Vol.175 (4), p.947-961.e17
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: 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 p38γ 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. [Display omitted] •Imidazole propionate levels are increased in subjects with type 2 diabetes (T2D)•Imidazole propionate is produced from histidine by T2D-associated bacteria•Imidazole propionate impairs glucose tolerance and insulin signaling•Imidazole propionate inhibits IRS via activation of p38γ/p62/mTORC1 Imidazole propionate, a metabolite produced by the gut microbiota, is elevated in type 2 diabetes and can directly impair glucose tolerance and insulin signaling.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

United States: Elsevier Inc

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