Rôle de la résistine hypothalamique dans l'installation de l’inflammation hypothalamique et l’insulino-résistance : impact de la consommation aigüe ou chronique d'un régime hyper lipidique

Abstract : Obesity is closely linked to a cluster of metabolic disorders including chronic low-grade inflammation and insulin resistance, which constitutes a principal risk factor for type 2 diabetes. In rodents, cumulative evidence support that the consumption of high fat diet (HFD) is among the most important nutritional factors predisposing to obesity associated insulin resistance and low-grade inflammation. Indeed, HFD induces hypothalamic inflammation and deregulates energy homeostasis control through the alteration of hypothalamic insulin and leptin responsiveness, considered as the main anorexigenic hormones. In addition, it has been shown that unlike peripheral inflammation, which occurs as a consequence of obesity, hypothalamic inflammation develops selectively in the hypothalamic arcuate nucleus (ARC) within the first days of HFD exposure. These data suggest that hypothalamic inflammation is a critical step in the early onset of the deregulation of energy homeostasis by HFD. The cellular and molecular mechanisms underlying obesity-induced hypothalamic inflammation are still not fully characterized. In rodents, resistin is described as a causal factor in obesitymediated insulin resistance and type 2 diabetes. Resistin is mainly secreted by adipose tissue in rodents but an endogenous expression of resistin was also reported in the hypothalamus. However, its action at the central level is not fully understood. Our group recently demonstrated that central resistin, via hypothalamic TLR4, promotes overall insulin resistance through the promotion of inflammatory pathway. In this context, we aimed to investigate the role of resistin/TLR4 pathway in HFD-induced hypothalamic inflammation and insulin resistance. In the present study we report for the first time that both short and long term HFD are associated with a significant increase of resistin expression throughout the MBH. Our results revealed a transient increase in resistin mRNA expression in the ARC after 3 days of HFD, followed by a decline to baseline at day 8 and an expression that increases again after 8 weeks of HFD. We showed that the increase of resistin expression is concomitant with short term HFD-induced ARC reactive gliosis, known to early disrupt energy balance and to predispose to obesity. Interestingly, our results revealed that resistin is expressed by POMC neurons which are critical for energy balance and tanycytes that have the specificity to contact both cerebro-spinal fluid and fenestrated capillary in the mediane eminence. Interestingly, we show that resistin induces tanycytes inflammation through TLR4 suggesting that resistin could promote inflammation in tanycytes in response to short term HFD. Additionally, we show that ICV resistin markedly increases inflammatory markers in the hypothalamic arcuate nucleus in association with reactive gliosis involving recruitment of both microglia and astrocytes. Interestingly, we report that the knockdown of TLR4 almost completely abolished resistin-dependent both hypothalamic inflammation and reactive gliosis. Our data demonstrate that restitin/TLR4 pathway could play a critical role in HFD-diet induced hypothalamic inflammation in response to short and long term HFD which predispose to obesity, a hallmark of metabolic syndrome.
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Sarah Al-Rifai. Rôle de la résistine hypothalamique dans l'installation de l’inflammation hypothalamique et l’insulino-résistance : impact de la consommation aigüe ou chronique d'un régime hyper lipidique. Biologie cellulaire. Université Paris-Saclay, 2019. Français. ⟨NNT : 2019SACLS095⟩. ⟨tel-02279990⟩

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