Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

被引：699

作者：

Koh, Ara ^{[1
,2
]}

Molinaro, Antonio ^{[1
,2
]}

Stahlman, Marcus ^{[1
,2
]}

Khan, Muhammad Tanweer ^{[1
,2
]}

Schmidt, Caroline ^{[1
,2
,3
]}

Manneras-Holm, Louise ^{[1
,2
]}

Wu, Hao ^{[1
,2
]}

Carreras, Alba ^{[1
,2
]}

Jeong, Heeyoon ^{[4
]}

Olofsson, Louise E. ^{[1
,2
]}

Bergh, Per-Olof ^{[1
,2
]}

Gerdes, Victor ^{[5
]}

Hartstra, Annick ^{[6
]}

de Brauw, Maurits ^{[5
]}

Perkins, Rosie ^{[1
,2
]}

Nieuwdorp, Max ^{[1
,2
,6
,7
]}

Bergstrom, Goran ^{[1
,2
,3
]}

Backhed, Fredrik ^{[1
,2
,8
]}

机构：

[1] Univ Gothenburg, Inst Med, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden

[2] Sahlgrens Univ Hosp, Gothenburg, Sweden

[3] Sahlgrens Univ Hosp, Dept Physiol, Gothenburg, Sweden

[4] Pohang Univ Sci & Technol, Dept Life Sci, Pohang 37673, South Korea

[5] Slotervaart Hosp, Amsterdam, Netherlands

[6] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands

[7] Free Univ Amsterdam, VU Univ Med Ctr, Amsterdam, Netherlands

[8] Univ Copenhagen, Fac Hlth Sci, Sect Metab Receptol & Enteroendocrinol, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

来源：

CELL | 2018年 / 175卷 / 04期

基金：

欧洲研究理事会; 瑞典研究理事会;

关键词：

GUT MICROBIOTA; SERUM METABOLOME; AMINO-ACIDS; PROTEIN; ACTIVATION; PATHWAY; AUTOPHOSPHORYLATION; OBESITY; IMPACT; IDENTIFICATION;

D O I：

10.1016/j.cell.2018.09.055

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：947 / +

页数：32

共 68 条

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