Department of Physiology, School of Medicine at Emory University, 615 Michael Street, Atlanta, GA, 30322-3110, USA.
Division of Pulmonary, Allergy and Critical Care Medicine, Emory University Emory, 615 Michael Street, Atlanta, GA, 30322, USA.
Alzheimers Res Ther. 2019 Dec 31;12(1):1. doi: 10.1186/s13195-019-0546-4.
Insulin impairment and inflammation are two features common to type 2 diabetes and Alzheimer's disease; however, the molecular and signaling interactions underlying this relationship are not well understood. Mounting evidence point to the associations between the disruption of metabolite processing in insulin impairment and neurodegenerative conditions such as Alzheimer's. Although the brain depends partially on metabolites processed in the periphery, to date, little is known about how soluble tumor necrosis factor signaling (solTNF) impacts integrated peripheral immune and metabolic feedback signals in states of energy overload and insulin insensitivity.
C57Bl/6J mice were fed a high-fat high-carbohydrate diet (HFHC) for 14 weeks. The brain-permeant biologic XPro1595® was used to block solTNF-dependent pathways. Metabolic and immune alterations were evaluated in the gut, liver, and brain. Behavioral tests were performed. Untargeted metabolomics was carried out in the plasma and liver.
HFHC diet promotes central insulin impairment and dysregulation of immune-modulatory gene expressed in the brain. Alteration of metabolites associated with type 2 diabetes and Alzheimer's such as butanoate, glutamate, biopterin, branched-chain amino acids, purines, and proteoglycan metabolism was observed in HFHC-fed mice. solTNF inhibition ameliorates hepatic metabolic disturbances and hepatic and intestinal lipocalin-2 levels, and decreases insulin impairment in the brain and behavioral deficits associated with HFHC diet.
Our novel findings suggest that HFHC diet impacts central insulin signaling and immune-metabolic interactions in a solTNF-dependent manner to increase the risk for neurodegenerative conditions. Our novel findings indicate that selective solTNF neutralization can ameliorate peripheral and central diet-induced insulin impairment and identify lipocalin-2 as a potential target for therapeutic intervention to target inflammation and insulin disturbances in obesogenic environments. Collectively, our findings identify solTNF as a potential target for therapeutic intervention in inflammatory states and insulin disturbances in obesogenic environments to lower risk for AD.
胰岛素功能障碍和炎症是 2 型糖尿病和阿尔茨海默病共有的两个特征；然而，这种关系背后的分子和信号相互作用尚不清楚。越来越多的证据表明，在胰岛素功能障碍和阿尔茨海默病等神经退行性疾病中，代谢物处理的中断与可溶性肿瘤坏死因子信号（solTNF）之间存在关联。尽管大脑部分依赖于在外周处理的代谢物，但迄今为止，人们对可溶性肿瘤坏死因子信号（solTNF）如何影响能量过载和胰岛素不敏感状态下整合的外周免疫和代谢反馈信号知之甚少。
C57Bl/6J 小鼠用高脂肪高碳水化合物饮食（HFHC）喂养 14 周。使用可穿透大脑的生物制剂 XPro1595® 阻断 solTNF 依赖性途径。评估肠道、肝脏和大脑中的代谢和免疫改变。进行行为测试。对血浆和肝脏进行非靶向代谢组学分析。
HFHC 饮食可促进大脑胰岛素功能障碍和免疫调节基因表达失调。在 HFHC 喂养的小鼠中观察到与 2 型糖尿病和阿尔茨海默病相关的代谢物改变，如丁酸盐、谷氨酸、生物喋呤、支链氨基酸、嘌呤和蛋白聚糖代谢。solTNF 抑制可改善肝代谢紊乱和肝肠脂联素-2 水平，并降低大脑胰岛素功能障碍和 HFHC 饮食相关的行为缺陷。
我们的新发现表明，HFHC 饮食以 solTNF 依赖的方式影响中枢胰岛素信号和免疫代谢相互作用，增加神经退行性疾病的风险。我们的新发现表明，选择性 solTNF 中和可改善外周和中枢饮食诱导的胰岛素功能障碍，并确定脂联素-2 作为治疗干预的潜在靶点，以针对肥胖环境中的炎症和胰岛素紊乱。总之，我们的研究结果表明，solTNF 是肥胖环境中炎症状态和胰岛素紊乱的潜在治疗靶点，可降低 AD 的风险。
Zotero 插件
