Dietary fat effect on brain immune response and inflammation

退伍军人的肥胖发生率高于美国普通人群。膳食脂肪影响 发展外周代谢疾病和认知障碍，例如阿尔茨海默病（AD）。 大脑的炎症（神经炎症），一种与进行性神经元损失相关的状态，已知是脑损伤的主要原因。 认知能力下降和肥胖的几率更高。虽然神经炎症通常随着年龄的增长而增加，但风险大大增加。 由于长期食用高饱和脂肪酸如棕榈酸的饮食而恶化。小胶质细胞 脑内常驻免疫细胞，在脑内神经炎症中起着不可或缺的作用，并代表了 饮食和神经炎性疾病之间的共同联系。小胶质细胞对环境有高度反应性 信号，如由饮食引起的信号。小胶质细胞对脑环境变化的反应是在多种神经元之间转换， 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。 依赖途径，从而激活促炎表型并增加促炎因子的释放。 炎性细胞因子炎症和脂质代谢的联系表明， 脂肪酸结合蛋白4（FABP 4）。我们首次证明FABP 4在小胶质细胞中表达， FABP 4的缺失导致线粒体解偶联蛋白2（UCP 2）的激活。具体地说， FABP 4的缺失导致细胞单不饱和脂肪酸（主要是C16：1）的增加， UCP 2的表达。此外，UCP 2的表达增加导致炎性细胞因子的表达减少。 小胶质细胞中的细胞因子。在外周巨噬细胞中，UCP 2的缺失增加了氧化应激，增强了NFκB， 途径，并增加炎性细胞因子的分泌。然而，这些途径还没有得到充分利用。 在小胶质细胞中探索。对于该应用重要的是，FABP 4的分子、遗传或药理学损失导致 在抗炎表型和抗炎小胶质细胞表型的转变，即使在存在 高饱和脂肪的饮食。 巨噬细胞中的炎症需要三羧酸循环（TCA）中的代谢状态变化。的 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主要转变。 磷酸化用于能量生产。事实上，这种表型转换的分子基础部分是由于 氧化还原环境中的UCP 2依赖性变化和细胞内代谢途径的后续变化。 我们的初步数据支持FABP 4-UCP 2轴通过关键参数的变化驱动TCA利用率的变化。 线粒体酶如免疫应答基因-1（Irg-1）。虽然这种代谢适应的转变 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明确。 因此，饮食诱导的神经炎症代表了大脑免疫反应与神经系统疾病之间的未探索的联系。 在认知能力下降的背景下，膳食脂肪的代谢过程，并可能代表一种新的临床 治疗靶点 我们的总体假设是，高饱和脂肪酸饮食改变了小胶质细胞的氧化还原状态，导致 代谢适应，促进神经炎症和随后的认知能力下降。为了验证这一点，我们将1） 确定饱和脂肪酸是否在体外改变小胶质细胞的代谢适应;以及2）测试饱和脂肪酸是否降低了小胶质细胞的代谢适应。 神经炎症预防FABP 4敲除（AKO）小鼠中饮食诱导的认知下降。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的脂质代谢和认知，以更好地 了解衰老、肥胖和记忆丧失之间的关系。我们的长期目标是发展有针对性的 用于治疗炎症诱导的神经变性和认知能力下降的疗法，以造福退伍军人 受到多种疾病的影响，包括肥胖和AD。

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.