Dietary Fat, Brain Inflammation, and Dopamine System Function

项目总结/摘要 众所周知，长期食用高饱和脂肪（SF）饮食会导致大脑炎症，最近， 已被证明会损害多巴胺神经传递，类似于慢性药物使用。脑成像研究表明， 肥胖会逐渐减少多巴胺的神经传递，但驱动这些变化的机制并不 知道的SF诱导的肥胖症的标志是胰岛素抵抗和慢性炎症，其影响胰岛素抵抗和慢性炎症。 脑和外周组织。胰岛素信号传导对于微调多巴胺神经传递至关重要， 触发饱腹感回路，但胰岛素信号被促炎细胞因子削弱。细胞因子释放 在大脑中的免疫细胞称为小胶质细胞和星形胶质细胞，这可以直接触发SF。这个项目 试图确定这些神经胶质免疫细胞是否以增加炎性细胞因子的方式对SF作出反应， 以及细胞因子的增加是单独改变多巴胺神经传递还是通过干扰胰岛素 发信号。确定神经胶质细胞在这一过程中的作用将提供一个治疗靶点， 多巴胺神经传递，恢复正常的饱腹感信号。我们还将探讨 抗炎不饱和脂肪酸，以减少大脑炎症和恢复多巴胺 神经传递我们假设，富含亚麻籽油的饮食，一种有效的抗炎来源， Omega 3脂肪酸，将减弱促炎细胞因子（TNF-α，IL-6和IL-1β）的作用， SF饮食，改善胰岛素敏感性，并恢复长期SF后多巴胺神经传递缺陷 摄入我们还将测试饱和脂肪引起的肥胖是否会干扰胰岛素- 诱导饱腹感。从该项目收集的数据将证明亚麻籽油治疗肥胖症的疗效- 多巴胺神经传递的相关变化，并将提供一种新的治疗方法，以防止过度- 吃最终，确定多巴胺神经传递的炎症的影响，并描述如何 这些多巴胺信号的变化干扰饱腹感，将帮助我们理解饮食诱导的肥胖 导致食物摄入失调，在生理需求得到满足时促进过度进食。

Project Summary/Abstract Prolonged consumption of a high saturated fat (SF) diet is known to cause brain inflammation, and has recently been shown to impair dopamine neurotransmission similar to chronic drug use. Brain imaging studies show that obesity gradually reduces dopamine neurotransmission, but mechanisms that drive these changes are not known. A hallmark of SF-induced obesity is insulin resistance and chronic inflammation that impacts both the brain and peripheral tissues. Insulin signaling is essential to fine tune dopamine neurotransmission and helps trigger satiety circuits, but insulin signaling is weakened by pro-inflammatory cytokines. Cytokines are released in the brain by immune cells called microglia and astrocytes, which can be directly triggered by SF. This project seeks to identify whether these glial immune cells respond to SF in a way that increases inflammatory cytokines, and whether the increase in cytokines alters dopamine neurotransmission alone or by interfering with insulin signaling. Determining the role of glial cells in this process would provide a therapeutic target to normalize dopamine neurotransmission in obesity, and restore normal satiety signals. We will also explore the effectiveness of anti-inflammatory unsaturated fatty acids to reduce brain inflammation and restore dopamine neurotransmission. We hypothesize that a diet enriched with flaxseed oil, a potent source of anti-inflammatory omega 3 fatty acids, will attenuate the actions of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) induced by the SF diet, improve insulin sensitivity, and restore deficits in dopamine neurotransmission after prolonged SF intake. We will also test whether inflammation caused by saturated fat-induced obesity interferes with insulin- induced satiety. Data collected from this project will demonstrate the efficacy of flaxseed oil to treat obesity- related changes in dopamine neurotransmission, and will provide a novel treatment approach to prevent over- eating. Ultimately, identifying the impact of inflammation of dopamine neurotransmission, and characterizing how these changes in dopamine signaling interfere with satiety will help us understand how diet-induced obesity leads to dysregulated food intake, promoting over-eating when physiological needs have been met.