Short-Term High-Fat Diet Consumption Reduces Hypothalamic Expression of the Nicotinic Acetylcholine Receptor α7 Subunit (α7nAChR) and Affects the Anti-inflammatory Response in a Mouse Model of Sepsis
Short-Term High-Fat Diet Consumption Reduces Hypothalamic Expression of the Nicotinic Acetylcholine Receptor α7 Subunit (α7nAChR) and Affects the Anti-inflammatory Response in a Mouse Model of Sepsis
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DOI：
10.3389/fimmu.2019.00565
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发表时间：
2019-03-22
影响因子：
7.3
通讯作者：
Torsoni, Marcio Alberto
中科院分区：
文献类型：
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作者：
Parras Souza, Anelise Cristina;Souza, Camilla Mendes;Torsoni, Marcio Alberto
脓毒症是住院患者死亡的主要原因之一，在肥胖症中观察到的慢性和低度炎症似乎使感染的易感性和发病率恶化。然而，关于短期高脂饮食（HFD）及其在脓毒症发展中的作用知之甚少。在这里，我们首次表明，短期HFD消费损害早期烟碱乙酰胆碱受体α 7亚基（α 7 nAChR）介导的信号传导，胆碱能抗炎通路的主要组成部分之一，重点是下丘脑炎症和先天性免疫反应。将小鼠随机分配至HFD或标准食物（SC）3天，随后通过致死性腹膜内（i. p.）注射脂多糖（LPS）或通过盲肠结扎和穿孔（CLP）手术。在单独的实验中，两组均接受LPS（i. p.）或LPS（i. p.）与选择性α nAChR激动剂PNU-282987（i. p.或脑室内; i. c. v.）联合，并在攻击后2小时处死。短期食用HFD显著降低了下丘脑和肝脏中的α 7 nAChR mRNA和蛋白水平（p < 0.05）。免疫荧光显微镜显示弓状核（ARC）中胆碱能受体烟碱α 7亚基（α 7 nAChR）+细胞减少（SC中α 7 nAChR+细胞= 216，HFD = 84），ARC（2.6倍）和正中隆起（ME）（1.6倍）中F4/80+细胞增加，这可能导致神经元损伤。神经胶质酸性蛋白（GFAP）+细胞和神经元核抗原（NeuN）+细胞也增加消费后的HFD。HFD喂养的小鼠在致死剂量的LPS后或CLP手术后迅速死亡（与SC相比2倍）。LPS攻击提高了两组中的大多数细胞因子水平;然而，在HFD喂养的小鼠中观察到更高水平的TNF-α（脾和肝）、IL-1 β和IL-6（在评价的所有组织中）。此外，PNU-282987给药（i. p.或i. c. v.）降低注射LPS后下丘脑中炎症标志物的水平。然而，当进行PNU-282987 i. c. v.注射时，HFD喂养小鼠的抗炎作用远小于SC喂养小鼠。在这里，我们提供的证据表明，短期HFD损害早期α 7 nAChR在中央和外周组织的表达，有助于败血症的死亡概率较高。
Sepsis is one of the leading causes of death in hospitalized patients and the chronic and low-grade inflammation observed in obesity seems to worsen susceptibility and morbidity of infections. However, little is known with respect to a short-term high-fat diet (HFD) and its role in the development of sepsis. Here, we show for the first time, that short-term HFD consumption impairs early nicotinic acetylcholine receptor alpha 7 subunit (alpha 7nAChR)-mediated signaling, one of the major components of the cholinergic anti-inflammatory pathway, with a focus on hypothalamic inflammation and innate immune response. Mice were randomized to a HFD or standard chow (SC) for 3 days, and sepsis was subsequently induced by a lethal intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) or by cecal ligation and puncture (CLP) surgery. In a separate experiment, both groups received LPS (i.p.) or LPS (i.p.) in conjunction with the selective a alpha nAChR agonist, PNU-282987 (i.p. or intracerebroventricular; i.c.v.), and were sacrificed 2 h after the challenge. Short-term HFD consumption significantly reduced the alpha 7nAChR mRNA and protein levels in the hypothalamus and liver (p < 0.05). Immunofluorescence microscopy demonstrated lower cholinergic receptor nicotinic alpha 7 subunit (alpha 7nAChR)+ cells in the arcuate nucleus (ARC) (alpha 7nAChR+ cells in SC = 216 and HFD = 84) and increased F4/80+ cells in the ARC (2.6-fold) and median eminence (ME) (1.6-fold), which can contribute to neuronal damage. Glial fibrillary acidic protein (GFAP)+ cells and neuronal nuclear antigen (NeuN)+ cells were also increased following consumption of HFD. The HFD-fed mice died quickly after a lethal dose of LPS or following CLP surgery (2-fold compared with SC). The LPS challenge raised most cytokine levels in both groups; however, higher levels of TNF-alpha (Spleen and liver), IL-1 beta and IL-6 (in all tissues evaluated) were observed in HFD-fed mice. Moreover, PNU-282987 administration (i.p. or i.c.v.) reduced the levels of inflammatory markers in the hypothalamus following LPS injection. Nevertheless, when the i.c.v. injection of PNU-282987 was performed the anti-inflammatory effect was much smaller in HFD-fed mice than SC-fed mice. Here, we provide evidence that a short-term HFD impairs early alpha 7nAChR expression in central and peripheral tissues, contributing to a higher probability of death in sepsis.