Role of new lipids FAHFAs in the brain and their involvement in pathological conditions.

新脂质 FAHFAs 在大脑中的作用及其与病理状况的关系。

• 批准号: 337847048
• 负责人: Dr. Maria Fernandez Rubin de Celis, Ph.D.
• 金额: --
• 依托单位: Beth Israel Deaconess Medical Center
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/337847048?language=en
• 关键词: Role; new; lipids; FAHFAs; brain

Several lipids species such as omega-3 fatty acids, phospholipids, sphingolipids and cholesterol play major roles on brain homeostasis and function. A novel class of signaling lipids constituted by a fatty-acid bound to a hydroxy-fatty acid (FAHFAs) was recently discovered by the hosting group. A subfamily of this lipid class, palmitic acid hydroxy-stearic acids (PAHSAs), was shown to exert antidiabetic and anti-inflammatory actions by promoting insulin-stimulated glucose uptake and insulin secretion and preventing dendritic cell and adipose tissue macrophage activations. These lipids are found in the major metabolic tissues such as the liver and white and brown adipose tissues and in the serum, where their levels strongly correlate with insulin sensitivity. Interestingly, preliminary data from the hosting group indicate that FAHFAs are also present in the brain, where they seem to be synthesized in situ and promote anti-inflammatory effects on astrocytes. In this project proposal, we aim to investigate the potential role of FAHFAs in brain function, cellular metabolism as well as potential implications of these lipids in brain inflammation and cognitive performance. We propose a comprehensive and sequential plan in order to address these questions. First to all, a detailed analysis of the brain distribution of the different FAHFA families will be performed in order to identify those subfamilies with highest concentrations, indicative of potential important functions. Secondly, we will characterize the effects of those FAHFAs on the activity of microglia, astrocytes and neurons. Thirdly, given previous reports suggesting alterations in cognitive performance and anxiety associated to states of insulin resistance in humans, we will analyse potential FAHFA-mediated effects on these brain disorders by using several behavior tests in lean and obesity-induced insulin resistant mice subjected to direct brain administration of FAHFAs. Findings derived from this project may shed light on novel lipid molecules participating in brain function and homeostasis and serve as potential therapeutic targets for brain-related disorders.

几种脂质种类如ω-3脂肪酸、磷脂、鞘脂和胆固醇对脑内稳态和功能起主要作用。由脂肪酸结合羟基脂肪酸（FAHFA）构成的一类新的信号脂质最近被主持小组发现。这种脂质类的一个亚家族，棕榈酸羟基硬脂酸（PAHSAs），显示通过促进胰岛素刺激的葡萄糖摄取和胰岛素分泌以及防止树突状细胞和脂肪组织巨噬细胞活化来发挥抗糖尿病和抗炎作用。这些脂质存在于主要代谢组织中，如肝脏和白色和棕色脂肪组织以及血清中，其水平与胰岛素敏感性密切相关。有趣的是，来自主持小组的初步数据表明，FAHFA也存在于大脑中，它们似乎是原位合成的，并促进对星形胶质细胞的抗炎作用。在这个项目提案中，我们的目标是研究FAHFA在脑功能，细胞代谢中的潜在作用，以及这些脂质在脑炎症和认知能力中的潜在影响。我们提出了一个全面和连续的计划，以解决这些问题。首先，将对不同FAHFA家族的大脑分布进行详细分析，以识别浓度最高的亚家族，表明潜在的重要功能。其次，我们将描述这些FAHFA对小胶质细胞、星形胶质细胞和神经元活性的影响。第三，鉴于先前的报告表明，认知能力和焦虑与人类胰岛素抵抗状态相关的改变，我们将分析FAHFA介导的对这些大脑疾病的潜在影响，通过使用几种行为测试，在瘦和肥胖诱导的胰岛素抵抗小鼠中直接给予FAHFA。来自该项目的发现可能揭示参与脑功能和稳态的新型脂质分子，并作为脑相关疾病的潜在治疗靶点。