Ceramide-Mediated Insulin Resistance and Impairment of Cognitive-Motor Functions
Ceramide-Mediated Insulin Resistance and Impairment of Cognitive-Motor Functions
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DOI：
10.3233/jad-2010-091726
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Wands, Jack R.
中科院分区：
文献类型：
--
作者：
de la Monte, Suzanne M.;Tong, Ming;Wands, Jack R.
肥胖、2型糖尿病（T2 DM）和非酒精性脂肪性肝炎（NASH）与认知障碍、脑胰岛素抵抗和神经退行性病变相关。最近的研究将这些影响与肝脏中神经酰胺原基因表达增加和血清中神经酰胺水平增加联系起来。由于神经酰胺是神经毒性的，并导致胰岛素抵抗，我们直接检查的作用，神经酰胺作为介质受损的信号和中枢神经系统功能，使用体内模型。通过腹膜内注射给予Long Evans大鼠幼仔C2Cer：N-乙酰神经鞘氨醇或其无活性的二氢神经酰胺类似物（C2 DCer）。对大鼠进行运动和认知功能的旋转棒和Morris水迷宫测试，并检查肝脏和大脑的组织病理学和胰岛素/IGF信号传导的完整性。C2Cer治疗引起高血糖症、高脂血症和轻度脂肪性肝炎，降低脑脂质含量，并增加肝、脑和血清中的神经酰胺水平。定量RTPCR分析显示，胰岛素和IGF-I信号传导所需的几个基因的表达发生了显着变化，多重ELISA证实了通过胰岛素或IGF-1受体，IRS-1和Akt在肝脏和大脑中的信号传导的抑制。最终，在外周来源如肝脏或脂肪组织中产生的有毒神经酰胺导致神经认知功能和胰岛素/IGF信号传导的持续损伤，这些信号传导是大脑中神经元存活、可塑性和髓鞘维持所需的。这些发现支持我们的假设，即通过增加毒性脂质/神经酰胺产生和穿过血脑屏障的转运实现的肝脏/外周组织-脑神经变性轴可以介导T2 DM和NASH中的认知障碍。
Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) are associated with cognitive impairment, brain insulin resistance, and neurodegeneration. Recent studies linked these effects to increased pro-ceramide gene expression in liver and increased ceramide levels in serum. Since ceramides are neurotoxic and cause insulin resistance, we directly examined the role of ceramides as mediators of impaired signaling and central nervous system function using an in vivo model. Long Evans rat pups were administered C2Cer:N-acetylsphinganine or its inactive dihydroceramide analog (C2DCer) by i.p. injection. Rats were subjected to rotarod and Morris water maze tests of motor and cognitive function, and livers and brains were examined for histopathology and integrity of insulin/IGF signaling. C2Cer treatment caused hyperglycemia, hyperlipidemia, and mild steatohepatitis, reduced brain lipid content, and increased ceramide levels in liver, brain, and serum. Quantitative RTPCR analysis revealed significant alterations in expression of several genes needed for insulin and IGF-I signaling, and multiplex ELISAs demonstrated inhibition of signaling through the insulin or IGF-1 receptors, IRS-1, and Akt in both liver and brain. Ultimately, the toxic ceramides generated in peripheral sources such as liver or adipose tissue caused sustained impairments in neuro-cognitive function and insulin/IGF signaling needed for neuronal survival, plasticity, and myelin maintenance in the brain. These findings support our hypothesis that a liver/peripheral tissue-brain axis of neurodegeneration, effectuated by increased toxic lipid/ceramide production and transport across the blood-brain barrier, could mediate cognitive impairment in T2DM and NASH.