Dietary fat effect on brain immune response and inflammation

膳食脂肪对大脑免疫反应和炎症的影响

• 批准号: 9565218
• 负责人: Tammy Angaline Butterick
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9565218
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Anti-inflammatory; Brain; Cells; Chronic; Classification; Clinical; Cognition; Cognition Disorders; Comorbidity; Consumption; Coupled; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Disease; Encephalitis; Environment; Enzymes; Ethnic Origin; Exhibits; Fatty Acids; Gene Expression; General Population; Genes; Glycolysis; Goals; Health; High Fat Diet; Immune; Immune response; Impaired cognition; In Vitro; Incidence; Inflammation; Inflammatory; Knock-out; Knowledge; Link; Memory Loss; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Microglia; Mitochondria; Molecular; Molecular Genetics; Monounsaturated Fatty Acids; Mus; Nerve Degeneration; Neurodegenerative Disorders; Nomenclature; Obesity; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Palmitic Acids; Pathway interactions; Peripheral; Pharmacogenetics; Pharmacology; Phenotype; Play; Population; Production; Risk; Risk Factors; Role; Saturated Fatty Acids; Signal Transduction; Stimulus; TLR4 gene; Technology; Testing; Time; UCP2 protein; Up-Regulation; Veterans; Work; base; brain cell; brain circuitry; cognitive development; cytokine; demographics; fatty acid-binding proteins; lipid metabolism; low socioeconomic status; macrophage; neuroinflammation; neuron loss; neurotoxic; novel; oxidation; prevent; protein expression; response; saturated fat; single-cell RNA sequencing; targeted treatment; therapeutic target

Veterans exhibit higher incidence of obesity than does the general US population. Dietary fats influence risk of developing peripheral metabolic diseases and cognitive disorders such as Alzheimer’s disease (AD). Inflammation of the brain (neuroinflammation), a state associated with progressive neuronal loss, is known to be heightened in cognitive decline and obesity. While neuroinflammation normally increases with age, risk is greatly exacerbated by chronic consumption of diets high in saturated fatty acids, such palmitic acid. Microglia, the resident immune cells of the brain, play an integral role in neuroinflammation in the brain and represent a common link between diet and neuroinflammatory diseases. Microglia are highly reactive to environmental signals such as those caused by diet. Microglia react to changes in brain milieu by transitioning between multiple states, including neurotoxic pro-inflammatory and neuroprotective anti-inflammatory microglial phenotypes. Palmitic acid directly affects immune cells through stimulation of microglial toll like receptor- 4 (TLR-4)- dependent pathways, thereby activating pro-inflammatory phenotypes and increasing the release of pro- inflammatory cytokines. The linkage of inflammation and lipid metabolism suggests a key unexplored role for fatty acid binding protein-4 (FABP4). We demonstrate for the first time that FABP4 is expressed in microglial cells, and that the loss of FABP4 leads to activation of mitochondrial uncoupling protein 2 (UCP2). Specifically, loss of FABP4 leads to an increase in cellular monounsaturated fatty acids (predominately C16:1) that upregulate the expression of UCP2. Moreover, increased expression of UCP2 leads to reduced expression of inflammatory cytokines in microglia. In peripheral macrophages, loss of UCP2 increases oxidative stress, potentiates the NFκB pathway, and increases secretion of inflammatory cytokines. However, these pathways have not been fully explored in microglia. Importantly for this application, molecular, genetic, or pharmacologic loss of FABP4 results in an anti-inflammatory phenotype and a shift to anti-inflammatory microglial phenotypes, even in the presence of a high saturated fat diet. Inflammation in macrophages requires metabolic state changes in the tricarboxylic cycle (TCA). The transition to pro-inflammatory microglial phenotypes is accompanied by a major shift from glycolysis to oxidative phosphorylation for energy production. Indeed, the molecular basis for this phenotypic switch is due in part to the UCP2-dependent change in redox environment and subsequent changes in intracellular metabolic pathways. Our preliminary data support that the FABP4-UCP2 axis drives shifts in TCA utilization via changes in key mitochondrial enzymes such as immune responsive gene-1 (Irg-1). While this shift in metabolic adaptation can regulate immune response in the development of metabolic syndrome, this mechanism is undefined in microglia. Diet-induced neuroinflammation thus represents an unexplored link between brain immune response and metabolic processes to dietary fat within the context of cognitive decline, and may represent a novel clinical therapeutic target. Our overall hypothesis is that diets high in saturated fatty acids alter microglial redox state, resulting in metabolic adaptations that promote neuroinflammation and subsequent cognitive decline. To test this, we will 1) Determine if saturated fatty acids alter metabolic adaptation in microglia in vitro; and 2) Test whether reduced neuroinflammation prevents diet-induced cognitive decline in FABP4 knockout (AKO) mice. Our short-term goal will be to utilize pharmacogenetic approaches to define lipid metabolism in microglia and cognition to better understand relationships between aging, obesity, and memory loss. Our long-term goal is to develop targeted therapies for the treatment of inflammation-induced neurodegeneration and cognitive decline to benefit Veterans impacted by multiple diseases, including obesity and AD.

退伍军人暴露于肥胖事件高于美国普通人群。饮食脂肪会影响风险 患有外周种代谢疾病和认知疾病，例如阿尔茨海默氏病（AD）。 大脑的炎症（神经炎症）是一种与进行性神经元丧失相关的状态，已知是 认知能力下降和肥胖。虽然神经炎症通常随着年龄的增长而增加，但风险很大 长期食用饱和脂肪酸（例如棕榈酸）的长期消费加剧。小胶质细胞 大脑的居民免疫电池，在大脑的神经炎症中起着不可或缺的作用，代表 饮食与神经炎性疾病之间的共同联系。小胶质细胞对环境高度反应 诸如饮食引起的信号。小胶质细胞通过在多个之间过渡来对脑环境的变化反应 状态，包括神经毒性促炎和神经保护性抗炎小胶质细胞表型。 棕榈酸直接通过刺激小胶质TOLL（如受体4（TLR-4） - 依赖途径，从而激活促炎的表型并增加了促进性表型 炎症细胞因子。炎症和脂质代谢的联系表明， 脂肪酸结合蛋白-4（FABP4）。我们首次证明Fabp4在小胶质细胞中表达 细胞，而FabP4的丧失会导致线粒体解偶联蛋白2（UCP2）的激活。具体来说， FABP4的损失导致细胞单不饱和脂肪酸的增加（主要是C16：1） UCP2的表达。此外，UCP2的表达增加导致炎症的表达降低 小胶质细胞中的细胞因子。在外围巨噬细胞中，UCP2的损失增加了氧化应激，潜在的NFκB潜在 途径，并增加炎症细胞因子的分泌。但是，这些途径尚未完全 在小胶质细胞中探索。重要的是，对于这种应用，分子，遗传或药物的结肠损失Fabp4结果 在抗炎表型和转向抗炎小胶质细胞表型中，即使在存在 高饱和脂肪饮食。 巨噬细胞的炎症需要三核周期（TCA）的代谢状态变化。这 从糖酵解到氧化的主要转变可以实现向促炎性小胶质细胞表型的过渡 能源生产的磷酸化。实际上，这种表型开关的分子基础部分​​是由于 氧化还原环境中UCP2依赖性变化以及细胞内代谢途径的随后变化。 我们的初步数据支持FABP4-UCP2轴通过关键的更改而驱动TCA利用率的变化 线粒体酶，例如免疫响应基因1（IRG-1）。代谢适应的这种转变可以 调节代谢综合征发展的免疫反应，这种机制在小胶质细胞中不确定。 因此，饮食引起的神经炎症代表了大脑免疫响应与 在认知能力下降的背景下，饮食脂肪的代谢过程可能代表一种新的临床 治疗靶标。 我们的总体假设是，饱和脂肪酸高的饮食改变了小胶质氧化还原状态，从而导致 促进神经炎症和随后认知能力下降的代谢适应。为了测试这一点，我们将1） 确定饱和脂肪酸是否在体外改变了小胶质细胞的代谢适应性； 2）测试是否减少 神经炎症可防止饮食引起的FABP4敲除（AKO）小鼠的认知能力下降。我们的短期目标 将利用药物遗传学方法来定义小胶质细胞和认知中的脂质代谢 了解衰老，肥胖和记忆力丧失之间的关系。我们的长期目标是发展目标 治疗炎症引起的神经退行性和认知能力下降的疗法，使退伍军人受益 受多种疾病的影响，包括肥胖和AD。