Radler M E, Wright B J, Walker F R, Hale M W, Kent S
School of Psychological Science, La Trobe University, Melbourne, VIC, Australia.
School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
Neuroscience. 2015 Jan 29;285:236-47. doi: 10.1016/j.neuroscience.2014.11.014. Epub 2014 Nov 15.
Calorie restriction (CR) increases longevity and elicits many health promoting benefits including delaying immunosenescence and reducing the incidence of age-related diseases. Although the mechanisms underlying the health-enhancing effects of CR are not known, a likely contributing factor is alterations in immune system functioning. CR suppresses lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines, blocks LPS-induced fever, and shifts hypothalamic signaling pathways to an anti-inflammatory bias. Furthermore, we have recently shown that CR attenuates LPS-stimulated microglial activation in the hypothalamic arcuate nucleus (ARC), a brain region containing neurons that synthesize neuropeptide Y (NPY), an orexigenic neuropeptide that is upregulated by a CR diet and has anti-inflammatory properties. To determine if increased NPY expression in the ARC following CR was associated with changes in microglial activation, a set of brain sections from mice that were exposed to 50% CR or ad libitum feeding for 28 days before being injected with LPS were immunostained for NPY. The density of NPY-immunolabeling was assessed across the rostrocaudal extent of the ARC and hypothalamic paraventricular nucleus (PVN). An adjacent set of sections were immunostained for ionized calcium-binding adapter molecule-1 (Iba1) and immunostained microglia in the ARC were digitally reconstructed to investigate the effects of CR on microglial morphology. We demonstrated that exposure to CR increased NPY expression in the ARC, but not the PVN. Digital reconstruction of microglia revealed that LPS increased Iba1 intensity in ad libitum fed mice but had no effect on Iba1 intensity in CR mice. CR also decreased the size of ARC microglial cells following LPS. Correlational analyses revealed strong associations between NPY and body temperature, and body temperature and microglia area. Together these results suggest that CR-induced changes in NPY are not directly involved in the suppression of LPS-induced microglial activation, however, NPY may indirectly affect microglial morphology through changes in body temperature.
热量限制（CR）可延长寿命，并带来许多促进健康的益处，包括延缓免疫衰老和降低与年龄相关疾病的发病率。尽管CR促进健康作用的潜在机制尚不清楚，但一个可能的促成因素是免疫系统功能的改变。CR可抑制脂多糖（LPS）诱导的促炎细胞因子释放，阻止LPS诱导的发热，并使下丘脑信号通路转向抗炎倾向。此外，我们最近发现，CR可减弱LPS刺激的下丘脑弓状核（ARC）中的小胶质细胞激活，ARC是一个包含合成神经肽Y（NPY）的神经元的脑区，NPY是一种食欲肽，在CR饮食中上调且具有抗炎特性。为了确定CR后ARC中NPY表达增加是否与小胶质细胞激活的变化有关，对一组在注射LPS前接受50%CR或随意进食28天的小鼠的脑切片进行NPY免疫染色。在ARC和下丘脑室旁核（PVN）的前后范围评估NPY免疫标记的密度。相邻的一组切片用离子钙结合衔接分子-1（Iba1）进行免疫染色，并对ARC中免疫染色的小胶质细胞进行数字重建，以研究CR对小胶质细胞形态的影响。我们证明，暴露于CR可增加ARC中NPY的表达，但不影响PVN。小胶质细胞的数字重建显示，LPS增加了随意进食小鼠的Iba1强度，但对CR小鼠的Iba1强度没有影响。CR还降低了LPS后ARC小胶质细胞的大小。相关性分析显示NPY与体温以及体温与小胶质细胞面积之间存在强关联。这些结果共同表明，CR诱导的NPY变化并不直接参与抑制LPS诱导的小胶质细胞激活，然而，NPY可能通过体温变化间接影响小胶质细胞形态。
