Interaction of high-fat diet and brain trauma alters adipose tissue macrophages and brain microglia associated with exacerbated cognitive dysfunction.
Interaction of high-fat diet and brain trauma alters adipose tissue macrophages and brain microglia associated with exacerbated cognitive dysfunction.
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高脂肪饮食和脑外伤的相互作用会改变脂肪组织巨噬细胞和脑小胶质细胞，从而加剧认知功能障碍。
DOI：
10.1101/2023.07.28.550986
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Stoica,BogdanA
中科院分区：
文献类型：
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作者：
Henry,RebeccaJ;Barrett,JamesP;Vaida,Maria;Khan,NiazZ;Makarevich,Oleg;Ritzel,RodneyM;Faden,AlanI;Stoica,BogdanA
肥胖增加了创伤性脑损伤（TBI）的发病率和死亡率。我们对大脑和脂肪组织的转录组学变化进行了详细分析，以研究高脂饮食诱导的肥胖（DIO）和TBI与中枢和外周炎症通路以及神经功能之间的相互作用。成年雄性小鼠在实验性TBI之前喂食高脂肪饮食（HFD）12周，并在损伤后继续。合并TBI和HFD导致Y-迷宫、新物体识别（NOR）和Morris水迷宫（MWM）认知功能测试中的累加功能障碍。我们还使用脑和总内脏脂肪组织（VAT）中的细胞区室的Nanostring面板进行高通量转录组分析，然后进行无监督聚类，主成分分析和IPA途径分析，以确定基因表达程序和分子途径活性的变化。在联合TBI-HFD后的慢性期期间，对皮质和海马以及内脏脂肪组织中的细胞群体的分析显示了中枢和外周小胶质细胞/巨噬细胞反应的扩增，包括选择基因表达特征和途径的超加性变化。这些数据表明，HFD诱导的肥胖和TBI可以独立地引发和支持脑小胶质细胞和内脏脂肪组织巨噬细胞中改变状态的发展，包括在神经退行性疾病中观察到的疾病相关小胶质细胞/巨噬细胞（DAM）表型。HFD和TBI之间的相互作用促进了向慢性反应性小胶质细胞/巨噬细胞转录组特征和相关的促炎性疾病改变状态的转变，这可能部分地成为认知缺陷恶化的基础。靶向HFD诱导的反应性细胞表型，包括外周脂肪组织巨噬细胞，可用于减少TBI后的小胶质细胞适应不良状态，减轻创伤后神经变性和神经功能障碍。
Obesity increases the morbidity and mortality of traumatic brain injury (TBI). We performed a detailed analysis of transcriptomic changes in the brain and adipose tissue to examine the interactive effects between high-fat diet-induced obesity (DIO) and TBI in relation to central and peripheral inflammatory pathways, as well as neurological function. Adult male mice were fed a high-fat diet (HFD) for 12 weeks prior to experimental TBI and continuing after injury. Combined TBI and HFD resulted in additive dysfunction in the Y-Maze, novel object recognition (NOR), and Morris water maze (MWM) cognitive function tests. We also performed high-throughput transcriptomic analysis using Nanostring panels of cellular compartments in the brain and total visceral adipose tissue (VAT), followed by unsupervised clustering, principal component analysis, and IPA pathway analysis to determine shifts in gene expression programs and molecular pathway activity. Analysis of cellular populations in the cortex and hippocampus as well as in visceral adipose tissue during the chronic phase after combined TBI-HFD showed amplification of central and peripheral microglia/macrophage responses, including superadditive changes in select gene expression signatures and pathways. These data suggest that HFD-induced obesity and TBI can independently prime and support the development of altered states in brain microglia and visceral adipose tissue macrophages, including the disease-associated microglia/macrophage (DAM) phenotype observed in neurodegenerative disorders. The interaction between HFD and TBI promotes a shift toward chronic reactive microglia/macrophage transcriptomic signatures and associated pro-inflammatory disease-altered states that may, in part, underlie the exacerbation of cognitive deficits. Targeting of HFD-induced reactive cellular phenotypes, including in peripheral adipose tissue macrophages, may serve to reduce microglial maladaptive states after TBI, attenuating post-traumatic neurodegeneration and neurological dysfunction.