Rôle de la synthase inductible du monoxyde d'azote dans les maladies proinflammatoires et la résistance à l'insuline associée à l'obésité

Authors: Centeno Baez, Carolina
Advisor: Marette, André
Abstract: Obesity is a complex pathology, with a multifactorial origin, as well as an independent risk factor for metabolic diseases such as type 2 diabetes. It has been suggested that obesity-associated chronic inflammation contributes to the development of insulin resistance. It has been shown that iNOS, an important enzyme involved in immune responses, has been implicated in the pathogenesis of obesity-associated insulin resistance. Results presented here contribute to better understand the implication of this enzyme in metabolic disorders and thus identify potential cellular targets that might counteract deleterious effects associated with its induction. In the first study, resveratrol was shown to inhibit iNOS induction as well as NO production in muscle and adipose tissue of LPS-treated mice. These effects were recapitulated in vitro. We have also demonstrated that iNOS inhibition by resveratrol involves AMPK but not SIRT1 activation in muscle cells. In the second study, we generated MYO-nos2-KO, HEPnos2-KO and ADPnos2-KO mice, where iNOS expression was specifically invalidated in myocytes, hepatocytes and adipocytes respectively. We have observed that iNOS deletion in myocytes, hepatocytes and adipocytes was not sufficient to counteract obesogenic-diet deleterious effects on insulin sensitivity and glucose tolerance. However, iNOS specific deletion in adipocytes seems to improve lipid metabolism. In our third chapter, we have shown that iNOS could be induced in adipose cells of human origin and that its expression in adipose tissue, was negatively correlated with plasma adiponectin levels of the subjects of the study. Overall, our results allow us to propose more specific targets where iNOS inhibition might be beneficial. Likewise, the results presented here contribute to the understanding of the potential role of this protein in the development of human metabolic disorders.
Document Type: Thèse de doctorat
Issue Date: 2015
Open Access Date: 23 April 2018
Permalink: http://hdl.handle.net/20.500.11794/26184
Grantor: Université Laval
Collection:Thèses et mémoires

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