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Doctoral thesis (Dissertations and theses)
Role of adipose tissue inflammation and NLRP3 inflammasome in the pathogenesis of metabolic syndrome and type 2 diabetes.
Esser, Nathalie
2014
 

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Keywords :
Adipose tissue; cytokines; macrophages; NLRP3 inflammasome; type 2 diabetes; metabolic syndrome
Abstract :
[en] It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, skeletal muscle and pancreas are themselves sites of inflammation in obesity. An infiltration of macrophages and other immune cells is observed in these tissues, associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory cytokine interleukin-1 beta (IL-1β) is involved in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. Obesity is a heterogeneous disease; some patients are obese but metabolically healthy (MHO) whereas others develop metabolic disorders (metabolically unhealthy or MUO). Adipose tissue is also heterogeneous; its visceral component is more associated with metabolic disorders than its subcutaneous component. The aim of this work is to assess whether differences in NLRP3 inflammasome activity and adipose cell composition play a role in such phenotypic and biochemical heterogeneities. MHO and MUO phenotypes were defined, respectively, as the absence and the presence of metabolic syndrome. Cellular composition and intrinsic inflammasome activity were investigated by flow cytometry, quantitative RT-PCR, ELISA and tissue culture studies in paired subcutaneous and visceral adipose tissues from 23 MUO, 21 MHO and 9 lean individuals. Relevant and significant differences were found among the three study groups, including increased secretion of IL-1β, increased expression of IL1B and NLRP3 mRNA, increased levels of adipose tissue macrophages and granulocytes, and decreased levels of regulatory T lymphocytes in the visceral adipose tissue of MUO patients compared with that of MHO and lean participants. Both caspase-1 activity and IL-1β release were higher in the macrophages derived from the visceral adipose tissue of MUO compared with MHO. Similar significant differences were showed between the subcutaneous and the visceral adipose tissues of the MUO subjects. In conclusion, the MUO phenotype seems to be associated with an increased activation of the NLPR3 inflammasome in macrophages infiltrating visceral adipose tissue, and a less favorable inflammatory profile compared with the MHO phenotype. Identification of the triggers that determine differential activation of the inflammasome between obesity phenotypes would likely help to better understand the pathophysiology of obesity-related metabolic disorders. Targeting inflammation, especially NLRP3 inflammasome, may offer potential novel therapeutic perspectives in the prevention and treatment of type 2 diabetes.
Research center :
GIGA-I3 - Giga-Infection, Immunity and Inflammation - ULiège
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Esser, Nathalie  ;  Centre Hospitalier Universitaire de Liège - CHU > Service de diabétologie, nutrition, maladies métaboliques
Language :
English
Title :
Role of adipose tissue inflammation and NLRP3 inflammasome in the pathogenesis of metabolic syndrome and type 2 diabetes.
Alternative titles :
[fr] Rôle de l'inflammation du tissu adipeux et de l'inflammasome NLRP3 dans la pathogénie du syndrome métabolique et du diabète de type 2.
Defense date :
June 2014
Institution :
ULiège - Université de Liège
Degree :
Docteur en sciences biomédicales et pharmaceutiques
Promotor :
PAQUOT, Nicolas ;  Centre Hospitalier Universitaire de Liège - CHU > Service de diabétologie, nutrition, maladies métaboliques
Piette, Jacques ;  Université de Liège - ULiège > GIGA > GIGA I3 - Virology and Immunology
President :
SCHEEN, André  ;  Centre Hospitalier Universitaire de Liège - CHU > Service de diabétologie, nutrition, maladies métaboliques
Secretary :
Legrand, Sylvie ;  Université de Liège - ULiège > GIGA > GIGA I3 - Immunometabolism and Nutrition
Jury member :
MOUTSCHEN, Michel  ;  Université de Liège - ULiège > Département des sciences cliniques > Immunopathologie - Maladies infectieuses et médecine interne générale
Geenen, Vincent ;  Centre Hospitalier Universitaire de Liège - CHU > Service d'endocrinologie clinique
Desmet, Christophe  ;  Université de Liège - ULiège > GIGA > GIGA I3 - Cellular and Molecular Immunology
Cnop, Miriam
Donath, Marc
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Fonds Léon Fredericq [BE]
Rotary Club de Liège
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