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.

退伍军人的肥胖发生率高于美国普通人群。膳食脂肪影响以下风险 患上外周代谢疾病和认知障碍，如阿尔茨海默病 (AD)。 大脑炎症（神经炎症）是一种与进行性神经元丧失相关的状态，已知 认知能力下降和肥胖加剧。虽然神经炎症通常随着年龄的增长而增加，但风险却很大 长期食用富含饱和脂肪酸（例如棕榈酸）的饮食会加剧这种情况。小胶质细胞 大脑的常驻免疫细胞，在大脑的神经炎症中发挥着不可或缺的作用，代表了 饮食与神经炎症疾病之间的常见联系。小胶质细胞对环境有高度反应 信号，例如由饮食引起的信号。小胶质细胞通过在多种神经元之间的转换来对大脑环境的变化做出反应 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。 棕榈酸通过刺激小胶质细胞 toll 样受体 - 4 (TLR-4) - 直接影响免疫细胞 依赖性途径，从而激活促炎表型并增加促炎物质的释放 炎症细胞因子。炎症和脂质代谢之间的联系表明了未探索的关键作用 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 细胞中，FABP4 的缺失会导致线粒体解偶联蛋白 2 (UCP2) 的激活。具体来说， FABP4 的缺失会导致细胞单不饱和脂肪酸（主要是 C16:1）增加，从而上调 UCP2的表达。此外，UCP2表达增加导致炎症细胞表达减少。 小胶质细胞中的细胞因子。在外周巨噬细胞中，UCP2 的缺失会增加氧化应激，增强 NFκB 途径，并增加炎症细胞因子的分泌。然而，这些途径尚未完全 在小胶质细胞中进行了探索。对于本应用来说重要的是，FABP4 结果的分子、遗传或药理学损失 抗炎表型和向抗炎小胶质细胞表型的转变，即使存在 高饱和脂肪饮食。 巨噬细胞的炎症需要三羧酸循环（TCA）中代谢状态的改变。这 向促炎性小胶质细胞表型的转变伴随着从糖酵解到氧化的重大转变 磷酸化以产生能量。事实上，这种表型转换的分子基础部分​​归因于 UCP2 依赖性氧化还原环境变化以及细胞内代谢途径的后续变化。 我们的初步数据支持 FABP4-UCP2 轴通过关键的变化来驱动 TCA 利用率的变化 线粒体酶，例如免疫反应基因 1 (Irg-1)。虽然代谢适应的这种转变可以 在代谢综合征的发展中调节免疫反应，这种机制在小胶质细胞中尚不清楚。 因此，饮食引起的神经炎症代表了大脑免疫反应和神经炎症之间尚未探索的联系。 在认知能力下降的背景下，膳食脂肪的代谢过程可能代表一种新的临床 治疗目标。 我们的总体假设是，富含饱和脂肪酸的饮食会改变小胶质细胞的氧化还原状态，从而导致 代谢适应会促进神经炎症和随后的认知能力下降。为了测试这一点，我们将 1) 确定饱和脂肪酸是否会改变体外小胶质细胞的代谢适应； 2）测试是否减少 神经炎症可预防 FABP4 敲除 (AKO) 小鼠饮食引起的认知能力下降。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，以更好地 了解衰老、肥胖和记忆丧失之间的关系。我们的长期目标是开发有针对性的 治疗炎症引起的神经退行性变和认知能力下降的疗法使退伍军人受益 受到多种疾病的影响，包括肥胖症和AD。