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Adipose tissue senescence in the context of high-fat diet-induced obesity and aging : mechanisms associated with the initiation of cellular senescence

Abstract : Obesity has dramatically increased worldwide and has become a major public health burden. Indeed, it increases the risk for death, mainly from cardiovascular disease. Physical inactivity and high energy in diet are known to promote oxidative stress and alter adipose tissue (AT) structure and function. In particular, our team has contributed to identify a critical role of visceral AT on cardiac fibrosis in addition to previous observations showing remote organ damage through a profibrotic and proinflammatory secretome of AT. Interestingly, these secreted factors are coincident with the accumulation of senescent cells in AT during both natural aging and obesity. Cellular senescence is associated with stable cell-cycle arrest induced by various stimuli such as telomere dysfunction and oxidative stress. Its functional implication is illustrated by observations that selective elimination of senescent cells prevents insulin resistance and delays the onset of age-related pathologies.However, time course of AT senescence and mechanisms underlying its initiation are yet unclear, as well as the precise identity of the cells affected within the AT. Therefore, my Doctoral project aimed to:-Establish the chronological order of events leading to visceral AT senescence in obesity-Identify the AT cells mainly affected by cellular senescence-Explore the role of senescent AT macrophages in the crosstalk between AT and heart.-Compare different strategies in order to mitigate visceral AT senescenceWe showed that AT senescence is an early and primary event that could orchestrate subsequent maladaptive changes in AT and heart function and remodelling. Besides, our results demonstrated the importance of early macrophage senescence in diet-induced and age-related cardiometabolic dysfunction and may shed new light on the search for developing better therapeutic options, including senolytic therapies, in the context of obesity in order to prevent cardiac and metabolic disorders
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Submitted on : Friday, May 13, 2022 - 6:41:22 PM
Last modification on : Monday, May 16, 2022 - 10:22:22 AM

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Zaineb Mezdari. Adipose tissue senescence in the context of high-fat diet-induced obesity and aging : mechanisms associated with the initiation of cellular senescence. Health. Université Paris-Est, 2021. English. ⟨NNT : 2021PESC0042⟩. ⟨tel-03667958⟩

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