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

 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有关，包括2型糖尿病，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过量对代谢的影响。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。这些回路在对饮食过量的反应中出错，促使人们提出了一个有趣的想法，即针对下丘脑功能障碍来减轻外周代谢功能障碍。 这项建议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。这一目标导致了对饮食诱导的炎症的关注，其在外周组织中涉及巨噬细胞，并已被靶向预防胰岛素抵抗和脂肪性肝炎。有趣的是，类似的“代谢性炎症”也发生在下丘脑中，并且涉及小胶质细胞、巨噬细胞的CNS类似物的积累。小鼠中强有力的初步数据显示，小胶质细胞决定饮食诱导的下丘脑炎症的严重程度，这表明靶向小胶质细胞对代谢有益的价值。 长链饱和脂肪酸（SFA）刺激巨噬细胞的炎症（M1）活化，也刺激M1活化下丘脑小胶质细胞。增加巨噬细胞在三酰甘油（TG）中储存膳食SFA的能力可以减少小鼠的外周代谢炎症和胰岛素抵抗，然而对小胶质细胞脂肪代谢几乎一无所知，这为发现提供了很好的机会。 该建议的中心假设是，膳食SFA穿过有孔血脑屏障进入下丘脑中基底，被小胶质细胞摄取，并压倒甘油脂质途径。这导致下丘脑小胶质细胞M1的激活和积累，产生一组确定的代谢异常。 该提案的目的是减轻SFA诱导的下丘脑小胶质细胞活化和随之而来的代谢功能障碍。它包含三个目标，使用创新的小鼠模型来测试中心假设并达到这一目标。第一个重点是循环脂蛋白在提供SFA下丘脑小胶质细胞，并针对小胶质细胞脂蛋白脂肪酶，以保护小胶质细胞从SFA诱导的激活。第二个确定限制小胶质细胞TG合成能力对SFA诱导的下丘脑炎症的影响。第三个使用新的工具来限制或自发诱导下丘脑小胶质细胞中的M1激活，以确定下丘脑小胶质细胞激活对葡萄糖，脂肪和能量代谢的影响。 这一提议的影响将开辟代谢研究的新前沿：操纵小胶质细胞营养代谢以控制下丘脑炎症。这一重点有望将小胶质细胞定义为减轻膳食SFA的有害代谢作用的靶点。通过验证控制小胶质细胞功能的新策略，拟议的工作可能会使从衰老到认知科学的其他领域受益。

 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.