Gut Microbiota Is a Key Modulator of Insulin Resistance in TLR 2 Knockout Mice

Abstract

Environmental factors and host genetics interact to control the gut microbiota, which may have a role in the development of obesity and insulin resistance. TLR2-deficient mice, under germ-free conditions, are protected from diet-induced insulin resistance. It is possible that the presence of gut microbiota could reverse the phenotype of an animal, inducing insulin resistance in an animal genetically determined to have increased insulin sensitivity, such as the TLR2 KO mice. In the present study, we investigated the influence of gut microbiota on metabolic parameters, glucose tolerance, insulin sensitivity, and signaling of TLR2-deficient mice. We investigated the gut microbiota (by metagenomics), the metabolic characteristics, and insulin signaling in TLR2 knockout (KO) mice in a non-germ free facility. Results showed that the loss of TLR2 in conventionalized mice results in a phenotype reminiscent of metabolic syndrome, characterized by differences in the gut microbiota, with a 3-fold increase in Firmicutes and a slight increase in Bacteroidetes compared with controls. These changes in gut microbiota were accompanied by an increase in LPS absorption, subclinical inflammation, insulin resistance, glucose intolerance, and later, obesity. In addition, this sequence of events was reproduced in WT mice by microbiota transplantation and was also reversed by antibiotics. At the molecular level the mechanism was unique, with activation of TLR4 associated with ER stress and JNK activation, but no activation of the IKKβ-IκB-NFκB pathway. Our data also showed that in TLR2 KO mice there was a reduction in regulatory T cell in visceral fat, suggesting that this modulation may also contribute to the insulin resistance of these animals. Our results emphasize the role of microbiota in the complex network of molecular and cellular interactions that link genotype to phenotype and have potential implications for common human disorders involving obesity, diabetes, and even other immunological disorders.

Full text

We don’t show the text of a retracted or withdrawn paper. The record stays, so citations to it can be checked.

Cited by papers we hold 30

• Taxonomic and Functional Fecal Microbiota Signatures Associated With Insulin Resistance in Non-Diabetic Subjects With Overweight/Obesity Within the Frame of the PREDIMED-Plus Study · 2022
  Not checked
• The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis · 2022
  No notice
• In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo · 2022
  No notice
• Role of Leptin in Inflammation and Vice Versa · 2020
  No notice
• Sex, gut microbiome, and cardiovascular disease risk · 2019
  No notice
• Blautia genus associated with visceral fat accumulation in adults 20–76 years of age · 2019
  No notice
• Nutrients Mediate Intestinal Bacteria–Mucosal Immune Crosstalk · 2018
  No notice
• Resveratrol, Metabolic Syndrome, and Gut Microbiota · 2018
  No notice
• Vitamin D: Nutrient, Hormone, and Immunomodulator · 2018
  No notice
• Nonalcoholic Fatty Liver Disease Is Exacerbated in High-Fat Diet-Fed Gnotobiotic Mice by Colonization with the Gut Microbiota from Patients with Nonalcoholic Steatohepatitis · 2017
  No notice
• Macrophage function in obesity-induced inflammation and insulin resistance · 2017
  No notice
• High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice · 2017
  No notice
• Next-Generation Beneficial Microbes: The Case of Akkermansia muciniphila · 2017
  No notice
• Interaction between gut microbiota and toll-like receptor: from immunity to metabolism · 2016
  No notice
• The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome · 2016
  No notice
• The role of Gut Microbiota in the development of obesity and Diabetes · 2016
  No notice
• Intestinal Epithelial Toll-Like Receptor 4 Signaling Affects Epithelial Function and Colonic Microbiota and Promotes a Risk for Transmissible Colitis · 2016
  No notice
• Role of Gut Microbiota in the Aetiology of Obesity: Proposed Mechanisms and Review of the Literature · 2016
  No notice
• Akkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism · 2016
  No notice
• The Macrophage Switch in Obesity Development · 2016
  No notice

and 10 more

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.