Leptin as a modulator of glial function in inflammation

瘦素是一种脂肪细胞衍生的能量调节激素，目前已被确定为生物体能量状态与其对入侵病原体发起有效宿主防御反应能力之间的重要接口。这一作用与最近描述的这种激素的功能有关，它是一种免疫调节剂，是外周和大脑中重要的免疫调节剂。我们是第一个描述瘦素和促炎细胞因子（如脑白细胞介素- 1ß）之间的直接功能关系的人之一，表明这种激素的食欲抑制作用是通过在大脑中诱导这种细胞因子来介导的。在随后的体外研究中，我们确定了瘦素在大脑中诱导IL-1成为小胶质细胞的细胞靶点，我们已经证明了小胶质细胞表达功能性瘦素受体。除了直接诱导IL-1外，我们还发现，将原代小胶质细胞与瘦素一起预先培养，使细胞对继发性免疫原性刺激（如细菌脂多糖（LPS））更具反应性，从而导致培养基中IL-1ß的输出增加数倍。这种效应似乎与瘦素引起的形态学变化有关。考虑到瘦素对小胶质细胞功能的明显调节作用，我们目前正在测试这样一个假设，即这些细胞长期暴露于高于正常浓度的这种激素中，比如长期食用高脂肪饮食（HFD），将导致它们的正常活动和细胞周期发生根本的、可能是不可逆转的改变。在最近的实验中，我们已经证实，食用HFD 1或3周可诱导更高的循环瘦素水平，并导致小胶质细胞的显著激活。这种活动的增加伴随着与小胶质细胞吞噬相关的蛋白表达的上调，在已知的具有显著成人神经原性活动的区域，包括下丘脑和海马，尤其强烈。在巢蛋白gfp阳性小鼠中，我们还观察到HFD诱导相同区域内巢蛋白（新生神经元的标记物）阳性细胞的表达显著增加。我们现在打算研究小胶质细胞的高活性是否在功能上与这些区域新生细胞的吞噬有关，以及这些事件的后果。为此，我们将采用多学科技术方法，包括尖端成像技术和许多转基因小鼠系，包括肥胖瘦素（ob/ob）缺陷小鼠

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.**