Leptin as a modulator of glial function in inflammation

瘦素作为炎症中神经胶质功能的调节剂

• 批准号: RGPIN-2015-04791
• 负责人: Luheshi, Giamal
• 金额: $ 2.4万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613168
• 关键词: Leptin; modulator; glial; function; inflammation

The adipocyte derived energy regulating hormone, leptin is now established as an important interface between the energy status of an organism and its ability to mount an effective host defense response against invading pathogens. This role is linked to the recently described function of this hormone as an immune modulator and an important regulator of immunity both in the periphery and the brain. We were amongst the first to describe a direct functional relationship between leptin and pro-inflammatory cytokines such as brain interleukin (IL)- 1ß by showing, that the appetite suppressing effects of this hormone were mediated via the induction of this cytokine in the brain. In subsequent in vitro studies we identified the cellular targets of leptin in the brain for the induction of IL-1 to be microglia, which we have shown to express the functional leptin receptor. In addition to the direct induction of IL-1 we discovered that pre-incubation of primary microglial cells in culture with leptin rendered the cells more reactive to secondary immunogenic stimuli such as bacterial lipopolysaccharide (LPS), which resulted in a several-fold increase in IL-1ß output in the culture medium. This effect appeared to be linked to morphological changes induced by leptin. Given this apparent modulatory effect of leptin on microglial function, we are currently testing the hypothesis that the prolonged exposure of these cells to higher than normal concentrations of this hormone, such as occurs following prolonged consumption of high fat diet (HFD), will results in a fundamental, and possibly irreversible, shift in their normal activity and cell cycle. In recent experiments we have confirmed that the consumption of HFD for 1 or 3 weeks induces higher circulating levels of leptin and results in significant activation of microglia. This increased activity, was accompanied by upregulations in the expression of proteins linked with microglial phagocytosis, was particularly intense in regions known for significant adult neurogenic activity, including the hypothalamus and hippocampus. Using Nestin-GFP positive mice we in addition observed a significant HFD induced increase in the expression of Nestin (marker for new born neurons) positive cells in the same regions. We now intend to investigate if the higher activity of microglia is functionally linked to phagocytosis of newborn cells in these regions and the consequences of these events. For this we will use a multidisciplinary technical approach including cutting edge imaging techniques and a number of transgenic mouse lines including the obese leptin (ob/ob) deficient mice.

脂肪细胞来源的能量调节激素，瘦素，现在被确立为生物体的能量状态和它的安装能力之间的重要界面。 对入侵病原体的有效宿主防御反应。这种作用与最近描述的这种激素作为免疫调节剂和外周和大脑中免疫的重要调节剂的功能有关。我们是第一个描述瘦素和促炎细胞因子如脑白细胞介素（IL）-1 β之间的直接功能关系的人，通过显示这种激素的食欲抑制作用是通过诱导这种细胞因子在脑中介导的。在随后的体外研究中，我们确定了瘦素在脑中诱导IL-1的细胞靶点是小胶质细胞，我们已经证明小胶质细胞表达功能性瘦素受体。除了IL-1的直接诱导，我们发现，与瘦素一起培养的原代小胶质细胞的预孵育使细胞对次级免疫原性刺激如细菌脂多糖（LPS）更具反应性，这导致培养基中IL-1 β的输出增加数倍。这种效应似乎与瘦素诱导的形态学变化有关。鉴于瘦素对小胶质细胞功能的这种明显的调节作用，我们目前正在测试这样一种假设，即这些细胞长期暴露于高于正常浓度的这种激素，例如长期食用高脂饮食（HFD）后发生的情况，将导致其正常活动和细胞周期的根本性且可能不可逆的转变。在最近的实验中，我们已经证实，消费HFD 1或3周诱导更高的瘦素循环水平，并导致小胶质细胞的显着激活。这种增加的活动，伴随着与小胶质细胞吞噬作用相关的蛋白质表达的上调，在已知具有显著成人神经原性活动的区域，包括下丘脑和海马中特别强烈。使用Nestin-GFP阳性小鼠，我们另外观察到HFD诱导的相同区域中Nestin（新生神经元的标志物）阳性细胞表达的显著增加。我们现在打算研究小胶质细胞的较高活性是否在功能上与这些区域中新生细胞的吞噬作用以及这些事件的后果有关。为此，我们将使用多学科的技术方法，包括尖端成像技术和一些转基因小鼠品系，包括肥胖瘦素（ob/ob）缺陷小鼠。