Rôle de modulateurs immunologiques et métaboliques dans le développement de l’obésité et de la résistance à l’insuline : administration de la rapamycine ou de probiotiques chez la souris obèse

Abstract : Obesity is characterized by a low-grade chronic inflammation reflected by increased blood levels of inflammatory factors, which are known to contribute to the development of metabolic complications such as insulin resistance and type 2 diabetes.Obesity-related inflammation is initiated by the accumulation of inflammatory immune cells within the adipose tissue as observed in obese subjects, contributing to alteration of the physiology and the metabolic homeostasis of the tissue. A better understanding of the mechanisms controlling the balance between adipose tissue immune cells and the interaction of these cells with the metabolic tissues (e.g. white adipose tissue) could lead to the development of immune-based new therapeutic strategies to treat metabolic complications associated with obesity.During my PhD thesis, we worked on two projects that both aimed at studying the link between immunity and metabolism. We studied the consequences of the treatment of obese mice with the immunomodulatory drug rapamycin (Part 1) and with probiotics having anti-inflammatory properties (Part 2).Part 1: Beneficial Metabolic Effects of Rapamycin are Associated with Enhanced Regulatory Cells in Diet-Induced Obese MiceThis part corresponded to my main project. We aimed to analyze the effect of rapamycin (or Sirolimus), on the inflammatory response and the metabolic status of high-fat diet fed mice. Rapamycin is an immunosuppressive drug commonly used in transplanted patients to prevent graft rejection. However, the effects of rapamycin on metabolism remain elusive and it has been reported that rapamycin may have pro-inflammatory and prodiabetic properties since some transplanted patients can develop diabetes and inflammatory diseases. Rapamycin is a specific inhibitor of mTOR (mechanistic Target Of Rapamycin), a highly conserved kinase which play a key role in both metabolism and immunity. Our aims were: 1) to define the metabolic consequences of long-term rapamycin administration and 2) to analyze the immune profile of treated animals.Part 2: A Probiotic Mixture Alleviates Diet-Induced Obesity and Insulin Resistance in Mice through Adipose Tissue Cell-RemodelingThe effects of probiotics on the development of obesity and its associated-metabolic complications are contradictory and thus remain to be clarified. In our study, we evaluated the consequences of the consumption of different strains of probiotics (or a combination of strains) selected for their anti-inflammatory properties, on the development of obesity and inflammation. We thus defined the metabolic and immune profile of probiotic-treated obese mice, mostly focusing on the adipose tissue. Finally, we attempted to identify the cellular and molecular mechanisms by which our selected probiotics exerted their metabolic and immune protective effects.
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Kassem Makki. Rôle de modulateurs immunologiques et métaboliques dans le développement de l’obésité et de la résistance à l’insuline : administration de la rapamycine ou de probiotiques chez la souris obèse. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2014. Français. ⟨NNT : 2014LIL2S006⟩. ⟨tel-01059209⟩

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