Identification of dietary lipid cues that regulate metabolism in Drosophila.

调节果蝇代谢的膳食脂质线索的鉴定。

• 批准号: 338683637
• 负责人: Dr. Marko Brankatschk, Ph.D.
• 金额: --
• 依托单位: Biotechnologisches Zentrum (Biotec)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/338683637?language=en
• 关键词: Identification; dietary; lipid; cues; regulate

Dietary lipids are one major element that defines the caloric content of our diet. In addition, recent studies identified lipids as cues capable to induce a cellular and systemic metabolic response. In the wild fruit flies feed on rotting fruits, a diet rich in calories with plant and fungal components. Fungal lipids are different from plant lipids; fungal fatty acids are shorter and more saturated, and contain fungal sterols rather than plant sterols. Dietary sterols are critical for Drosophila membrane and hormone production because flies are sterol auxotrophs. To study how different lipid compositions affect metabolism in flies I have created two new recipes, plant and yeast food. Both diets share a very similar high caloric richness and have almost identical protein/sugar/lipid ratios. I have discovered that yeast lipids elevate systemic Insulin signaling. The high Insulin signaling levels result in fast development and high reproductive rates, but decrease the average lifespan of adult fruit flies. I found that lipoprotein particles are required to convey the dietary yeast lipid signal to Insulin producing neurons. To reach their neuronal targets, a specific lipoprotein particle called LTP needs to cross the Blood Brain Barrier, which controls all traffic into the brain. I have shown that nutritional yeast lipids elevate intracellular Calcium levels in Blood Brain Barrier cells and that high intracellular Calcium levels are required for the targeted receptor mediated translocation of the specific lipoprotein particle LTP (Lipid transport protein). In the brain, LTP enriches on distinct neurons that are directly connected to Insulin producing cells. My data suggest that the activity of these LTP positive neurons triggers the release of Insulin into circulation.I would now like to understand how these lipids activate BBB cells, and the mechanisms that then allow the transport of LTP across the BBB to specific neurons with the brain. To do so, I propose the following aims:1. To identify dietary lipids that activate Blood Brain Barrier cells, and the mechanisms by which they act (in flies and in a vertebrate cell culture model). 2. To map the glio-neuronal network that connects Blood Brain Barrier cells with specific neurons.3. To identify membrane traffic routes that deliver LTP across the Blood Brain Barrier (in response metabolic changes). My grant proposal outlines here detailed protocols to isolate and identify dietary lipids that activate Calcium signaling in BBB cells, and describes strategies to discriminate between structural lipids (that modulate the composition of plasma membranes to induce cell reactivity) or lipid signal cues. It describes a cutting edge genetic approach to identify the pattern and plasticity of connections between BBB cells and specific neurons. This proposal also outlines how I will use a library of endogenously YFP-tagged Rab proteins to identify membrane trafficking routes across the BBB used by LTP.

膳食脂质是定义我们饮食中卡路里含量的一个主要元素。此外，最近的研究确定脂质作为能够诱导细胞和全身代谢反应的线索。在野外，果蝇以腐烂的水果为食，这种食物富含植物和真菌成分的卡路里。真菌脂质与植物脂质不同;真菌脂肪酸较短且更饱和，并且含有真菌甾醇而不是植物甾醇。膳食固醇对果蝇膜和激素产生至关重要，因为果蝇是固醇营养缺陷型。为了研究不同的脂质成分如何影响苍蝇的新陈代谢，我创造了两种新的食谱，植物和酵母食品。两种饮食都有非常相似的高热量丰富度，并且具有几乎相同的蛋白质/糖/脂质比例。我已经发现酵母脂质提高全身胰岛素信号。高胰岛素信号水平导致快速发育和高繁殖率，但降低了成年果蝇的平均寿命。我发现脂蛋白颗粒是将饮食酵母脂质信号传递给产生胰岛素的神经元所必需的。为了到达它们的神经靶点，一种称为LTP的特定脂蛋白颗粒需要穿过血脑屏障，血脑屏障控制着进入大脑的所有交通。我已经表明，营养酵母脂质提高血脑屏障细胞中的细胞内钙水平，并且高细胞内钙水平是特定脂蛋白颗粒LTP（脂质转运蛋白）的靶向受体介导的易位所需的。在大脑中，LTP富集在与胰岛素产生细胞直接连接的不同神经元上。我的数据表明，这些LTP阳性神经元的活动触发胰岛素释放到循环中。我现在想了解这些脂质如何激活BBB细胞，以及随后允许LTP穿过BBB运输到大脑特定神经元的机制。 为此，我提出以下目标：1。确定激活血脑屏障细胞的膳食脂质及其作用机制（在果蝇和脊椎动物细胞培养模型中）。2.绘制连接血脑屏障细胞与特定神经元的胶质神经元网络.确定传递LTP穿过血脑屏障的膜交通路线（响应代谢变化）。我的资助提案在此概述了分离和鉴定激活BBB细胞中钙信号传导的膳食脂质的详细方案，并描述了区分结构脂质（调节质膜组成以诱导细胞反应性）或脂质信号线索的策略。它描述了一种尖端的遗传学方法来识别BBB细胞和特定神经元之间连接的模式和可塑性。该提案还概述了我将如何使用内源性YFP标记的Rab蛋白库来识别LTP所使用的跨BBB的膜运输路线。

项目成果

Selective Phosphorylation of Akt/Protein-Kinase B Isoforms in Response to Dietary Cues

• DOI: 10.3389/fcell.2019.00206
• 发表时间: 2019-10
• 期刊: Frontiers in Cell and Developmental Biology
• 影响因子: 5.5
• 作者: L. Trautenberg;E. Prince;Cornelia Maas;Nora Beier;Freya Honold;M. Grzybek;M. Brankatschk