Microglia: dietary fat-sensitive mediators of inflammation and metabolic disease

小胶质细胞：炎症和代谢疾病的膳食脂肪敏感介质

• 批准号: 9231449
• 负责人: SUNEIL Krishna KOLIWAD
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231449
• 关键词: Aging; Area; Astrocytes; Blood - brain barrier anatomy; Body Weight; Brain; Brain region; Buffers; Carotid Artery Ulcerating Plaque; Cellular Stress; Chronic; Cognitive Science; Data; Development; Diet; Dietary Fats; Disease; Eating; Energy Metabolism; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Gliosis; Goals; Health; Hypothalamic dysfunction; Hypothalamic structure; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Insulin Resistance; Joints; Link; Lipoproteins; Macronutrients Nutrition; Macrophage Activation; Manuscripts; Mediating; Medical; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Microglia; Mind; Minor; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Pathway interactions; Peripheral; Pharmaceutical Preparations; Positioning Attribute; Process; Public Health; Publications; Recommendation; Research; Role; Saturated Fatty Acids; Severities; Steatohepatitis; System; Techniques; Testing; Therapeutic; Thermogenesis; Tissues; Triglycerides; Work; analog; blood glucose regulation; cell type; dietary excess; frontier; glucose metabolism; innovation; insulin sensitivity; interest; lipid metabolism; lipoprotein lipase; macrophage; metabolic rate; mouse model; neurophysiology; nutrient metabolism; prevent; public health relevance; response; saturated fat; sugar; tool

 DESCRIPTION (provided by applicant): Diet-induced obesity is linked to increasingly prevalent metabolic diseases, including diabetes type 2, and current medications and dietary recommendations have not stemmed this tide. New, effective ways are therefore needed to reduce the metabolic impact of dietary excess. In response, a new wave of research is focusing on circuits in the hypothalamus, a brain area controlling food intake, body weight, and intermediary metabolism. These circuits go awry in response to dietary excess, prompting the intriguing idea of targeting hypothalamic dysfunction to lessen peripheral metabolic dysfunction. The long-term goal of this proposal is to control diet-induced hypothalamic dysfunction in order to limit metabolic disease. This goal has led to a focus on diet-induced inflammation, which in peripheral tissues involves macrophages and has been targeted to prevent insulin resistance and steatohepatitis. Interestingly, similar "metabolic inflammation" also occurs in the hypothalamus, and involves the accumulation of microglia, CNS analogs of macrophages. Strong preliminary data in mice reveal that microglia determine the severity of diet-induced hypothalamic inflammation, pointing to the value of targeting microglia for metabolic benefit. Long-chain saturated fatty acids (SFAs), which stimulate the inflammatory (M1) activation of macrophages, also stimulate the M1 activation hypothalamic microglia. Increasing the capacity of macrophages to store dietary SFAs in triacylglycerol (TG) reduces peripheral metabolic inflammation and insulin resistance in mice, however nearly nothing is known about microglial fat metabolism, providing a great opportunity for discovery. The central hypothesis of this proposal is that dietary SFAs traverse a fenestrated blood-brain barrier to enter the mediobasal hypothalamus, are taken up by microglia, and overwhelm glycerolipid pathways. This leads to hypothalamic microglial M1 activation and accumulation, producing a defined set of metabolic abnormalities. The objective of this proposal is to mitigate SFA-induced hypothalamic microglial activation and consequent metabolic dysfunction. It contains three aims, using innovative mouse models, to test the central hypothesis and reach this objective. The first focuses on circulating lipoproteins in delivering SFAs to hypothalamic microglia, and targets microglial lipoprotein lipase in order to protect microglia from SFA-induced activation. The second determines the impact of limiting microglial TG synthesis capacity on SFA-induced hypothalamic inflammation. The third uses new tools to limit or spontaneously induce M1 activation in hypothalamic microglia in order to determine the impact of hypothalamic microglial activation on glucose, fat, and energy metabolism. The impact of this proposal will be to open up a new frontier in metabolic research: that of manipulating microglial nutrient metabolism to control hypothalamic inflammation. This focus holds promise to define microglia as targets to mitigate the detrimental metabolic effects of dietary SFAs. By validating new strategies to control microglial function, the proposed work may benefit other areas from aging to cognitive sciences.

 描述（由申请人提供）：饮食引起的肥胖与日益流行的代谢疾病（包括 2 型糖尿病）有关，目前的药物和饮食建议尚未阻止这一趋势，因此需要新的有效方法来减少饮食对代谢的影响。作为回应，新一波的研究集中在下丘脑的回路上，下丘脑是控制食物摄入、体重和中间代谢的大脑区域，这些回路会因饮食过量而出错，从而引发了“靶向”这一有趣的想法。该提案的长期目标是控制饮食引起的下丘脑功能障碍，以限制代谢性疾病。这一目标引起了人们对饮食引起的炎症的关注，这种炎症在外周组织中涉及巨噬细胞。类似地，类似的“代谢炎症”也发生在下丘脑，并涉及小胶质细胞（巨噬细胞的中枢神经系统类似物）的积累。小胶质细胞决定了饮食引起的下丘脑炎症的严重程度，这表明长链饱和脂肪酸 (SFA) 可以刺激巨噬细胞的炎症 (M1) 激活，也可以刺激下丘脑小胶质细胞的 M1 激活。增加巨噬细胞将饮食中的 SFA 储存在三酰甘油 (TG) 中的能力，可减少小鼠的外周代谢炎症和胰岛素抵抗，但对小胶质细胞脂肪代谢几乎一无所知，这提供了该提议的中心假设是，饮食中的 SFA 穿过有孔的血脑屏障，进入下丘脑内侧基底层，被小胶质细胞吸收，并压倒甘油脂途径，这导致下丘脑小胶质细胞 M1 激活和积累，产生。该提案的目的是通过创新来减轻 SFA 诱导的下丘脑小胶质细胞激活和随之而来的代谢功能障碍。小鼠模型，以测试中心假设并实现这一目标，第一个重点是循环脂蛋白将 SFA 传递到下丘脑小胶质细胞，并以小胶质细胞脂蛋白脂肪酶为目标，以保护小胶质细胞免受 SFA 诱导的激活。第三个研究使用新工具来限制或自发诱导下丘脑小胶质细胞中的 M1 激活，以确定下丘脑的影响。该提案的影响将开辟代谢研究的新领域：操纵小胶质细胞营养代谢来控制下丘脑炎症。这一重点有望将小胶质细胞定义为减轻炎症的目标。通过验证控制小胶质细胞功能的新策略，这项工作可能有益于从衰老到认知科学的其他领域。