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| Author(s): |
Andréa Moro Caricilli
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2012-02-15 |
| Examining board members: |
Mario José Abdalla Saad;
Sergio Atala Dib;
Antonio Carlos Boschiero;
Regina Celia Santiago Moises;
Licio Augusto Velloso
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| Advisor: | Mario José Abdalla Saad |
| 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. Diet-induced obese mice, acutely treated with TLR2 oligonucleotide antisense during 4 days showed increased insulin sensitivity and signaling in muscle and white adipose tissue. 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 molecular level the mechanism was unique with activation of TLR4, associated with ER stress and JNK activation, but no activation of the IKK?-I?B-NF?B 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 (AU) | |