Lipodystrophies are clinically heterogeneous acquired or inherited disorders characterized by selective loss of the adipose tissue. Non-invasive in vivo phenotyping of adipose tissue deposits in small animal models of...Lipodystrophies are clinically heterogeneous acquired or inherited disorders characterized by selective loss of the adipose tissue. Non-invasive in vivo phenotyping of adipose tissue deposits in small animal models of the disease is studied using 7T magnetic resonance imaging （MRI）. Pseudo image and multi-weight MRI methods show that the fat of seipin mice is virtually absent compared with WT mice. The three-dimensional （3-D） small animal visualization system for 7T MRI developed in this project facilitates to obtain the interested feature with stroke-based classification method. Student＇s t-test statistic result confirms that total fat and subcutaneous fat are less in seipin mice than those in WT mice. However, the visceral fat difference is not found in the experiment. Based on 7T MIRI, the study gives more reliable information on location and lipid contents of the tissue about seipin mice, thus it is important to explore the pathophysiological characteristics of the disease.展开更多
目的:探究内质网膜蛋白编码基因seipin杂合性缺失对APP/PS1小鼠认知功能的影响。方法:记录5月龄野生型(WT)、APP/PS1、seipin^(+/-)/APP/PS1小鼠体重和随机血糖,并进行腹腔葡萄糖耐量试验(IPGTT)和腹腔胰岛素耐量试验(IPITT)观察糖代谢...目的:探究内质网膜蛋白编码基因seipin杂合性缺失对APP/PS1小鼠认知功能的影响。方法:记录5月龄野生型(WT)、APP/PS1、seipin^(+/-)/APP/PS1小鼠体重和随机血糖,并进行腹腔葡萄糖耐量试验(IPGTT)和腹腔胰岛素耐量试验(IPITT)观察糖代谢的变化;运用Morris水迷宫(MWM)评估小鼠的认知能力;应用免疫组织化学法检测小鼠脑内β-淀粉样蛋白(Aβ)斑块沉积水平;通过Western Blot检测小鼠前额叶皮层胰岛素信号通路相关蛋白的变化;运用免疫荧光法检测小鼠前额叶皮层中Iba-1的表达并采用real time RT-PCR检测炎症相关因子的mRNA水平。结果:各组小鼠的体重和随机血糖无明显差异。seipin^(+/-)/APP/PS1组糖耐量曲线下面积(AUC)和胰岛素耐量AUC显著大于APP/PS1组(P<0.05)。MWM反向阶段seipin^(+/-)/APP/PS1组逃避潜伏期较APP/PS1和WT组显著增加,且在SE象限新平台的游程比、穿梭新平台所在位置次数均较APP/PS1和WT组显著降低(P<0.05)。同时我们还发现相较APP/PS1组,seipin^(+/-)/APP/PS1组前额叶皮层Aβ斑块数量显著增加(P<0.05),p-IRS1水平升高(P<0.05),p-Akt水平降低(P<0.05),且激活态小胶质细胞显著增多,iNOS、IL-1β、TNF-α和IL-6 mRNA表达显著增高(P<0.05)。结论:内质网膜蛋白seipin杂合性缺失可诱导APP/PS1小鼠早期外周糖代谢异常,从而影响前额叶皮层胰岛素代谢促使Aβ沉积,促进炎症因子表达,导致小鼠认知灵活性障碍。展开更多
Seipin plays a vital role in lipid droplet homeostasis,and its deficiency causes congenital generalized lipodystrophy type II in humans.It is not known whether the physiological defects are all caused by cellular lipi...Seipin plays a vital role in lipid droplet homeostasis,and its deficiency causes congenital generalized lipodystrophy type II in humans.It is not known whether the physiological defects are all caused by cellular lipid droplet defects.Loss-of-function mutation of seip-1,the Caenorhabditis elegans seipin ortholog,causes embryonic lethality and lipid droplet abnormality.We uncover nhr-114 and spin-4 as two suppressors of seip-1 embryonic lethality.Mechanistically,nhr-114 and spin-4 act in the“B12-one-carbon cycle-phosphatidylcholine(PC)”axis,and reducing PC synthesis suppresses the embryonic lethality of seip-1 mutants.Conversely,PC deficiency enhances the lipid droplet abnormality of seip-1 mutants.The suppression of seip-1 embryonic lethality by PC reduction requires polyunsaturated fatty acid.In addition,the suppression is enhanced by the knockdown of phospholipid scramblase epg-3.Therefore,seipin and PC exhibit opposite actions in embryogenesis,while they function similarly in lipid droplet homeostasis.Our results demonstrate that seipin-mediated embryogenesis is independent of lipid droplet homeostasis.展开更多
基金Supported by the National Natural Science Foundation of China (30830039)the National High Technology Research and Development Program of China ("863"Program) (2007AA02Z211)~~
文摘Lipodystrophies are clinically heterogeneous acquired or inherited disorders characterized by selective loss of the adipose tissue. Non-invasive in vivo phenotyping of adipose tissue deposits in small animal models of the disease is studied using 7T magnetic resonance imaging （MRI）. Pseudo image and multi-weight MRI methods show that the fat of seipin mice is virtually absent compared with WT mice. The three-dimensional （3-D） small animal visualization system for 7T MRI developed in this project facilitates to obtain the interested feature with stroke-based classification method. Student＇s t-test statistic result confirms that total fat and subcutaneous fat are less in seipin mice than those in WT mice. However, the visceral fat difference is not found in the experiment. Based on 7T MIRI, the study gives more reliable information on location and lipid contents of the tissue about seipin mice, thus it is important to explore the pathophysiological characteristics of the disease.
文摘目的:探究内质网膜蛋白编码基因seipin杂合性缺失对APP/PS1小鼠认知功能的影响。方法:记录5月龄野生型(WT)、APP/PS1、seipin^(+/-)/APP/PS1小鼠体重和随机血糖,并进行腹腔葡萄糖耐量试验(IPGTT)和腹腔胰岛素耐量试验(IPITT)观察糖代谢的变化;运用Morris水迷宫(MWM)评估小鼠的认知能力;应用免疫组织化学法检测小鼠脑内β-淀粉样蛋白(Aβ)斑块沉积水平;通过Western Blot检测小鼠前额叶皮层胰岛素信号通路相关蛋白的变化;运用免疫荧光法检测小鼠前额叶皮层中Iba-1的表达并采用real time RT-PCR检测炎症相关因子的mRNA水平。结果:各组小鼠的体重和随机血糖无明显差异。seipin^(+/-)/APP/PS1组糖耐量曲线下面积(AUC)和胰岛素耐量AUC显著大于APP/PS1组(P<0.05)。MWM反向阶段seipin^(+/-)/APP/PS1组逃避潜伏期较APP/PS1和WT组显著增加,且在SE象限新平台的游程比、穿梭新平台所在位置次数均较APP/PS1和WT组显著降低(P<0.05)。同时我们还发现相较APP/PS1组,seipin^(+/-)/APP/PS1组前额叶皮层Aβ斑块数量显著增加(P<0.05),p-IRS1水平升高(P<0.05),p-Akt水平降低(P<0.05),且激活态小胶质细胞显著增多,iNOS、IL-1β、TNF-α和IL-6 mRNA表达显著增高(P<0.05)。结论:内质网膜蛋白seipin杂合性缺失可诱导APP/PS1小鼠早期外周糖代谢异常,从而影响前额叶皮层胰岛素代谢促使Aβ沉积,促进炎症因子表达,导致小鼠认知灵活性障碍。
基金supported by the National Natural Science Foundation of China(9195420001)the Ministry of Science and Technology of China(2018YFA0506902).
文摘Seipin plays a vital role in lipid droplet homeostasis,and its deficiency causes congenital generalized lipodystrophy type II in humans.It is not known whether the physiological defects are all caused by cellular lipid droplet defects.Loss-of-function mutation of seip-1,the Caenorhabditis elegans seipin ortholog,causes embryonic lethality and lipid droplet abnormality.We uncover nhr-114 and spin-4 as two suppressors of seip-1 embryonic lethality.Mechanistically,nhr-114 and spin-4 act in the“B12-one-carbon cycle-phosphatidylcholine(PC)”axis,and reducing PC synthesis suppresses the embryonic lethality of seip-1 mutants.Conversely,PC deficiency enhances the lipid droplet abnormality of seip-1 mutants.The suppression of seip-1 embryonic lethality by PC reduction requires polyunsaturated fatty acid.In addition,the suppression is enhanced by the knockdown of phospholipid scramblase epg-3.Therefore,seipin and PC exhibit opposite actions in embryogenesis,while they function similarly in lipid droplet homeostasis.Our results demonstrate that seipin-mediated embryogenesis is independent of lipid droplet homeostasis.
