Palmitate alters the rhythmic expression of molecular clock genes and orexigenic neuropeptide Y mRNA levels within immortalized, hypothalamic neurons
Palmitate alters the rhythmic expression of molecular clock genes and orexigenic neuropeptide Y mRNA levels within immortalized, hypothalamic neurons
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DOI：
10.1016/j.bbrc.2011.08.103
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发表时间：
2011-09-30
影响因子：
3.1
通讯作者：
Belsham, Denise D.
中科院分区：
文献类型：
--
作者：
Fick, Laura J.;Fick, Gordon H.;Belsham, Denise D.
下丘脑内能量稳态的控制受到稳态激素、营养素和改变进食行为的神经肽表达的调节控制。棕榈酸盐是饮食和脂肪酸生物合成中的主要饱和脂肪酸，其水平升高会改变细胞功能。例如，参与胰岛素抵抗发展的一个关键机制是通过增加循环饱和脂肪酸的脂毒性。虽然许多研究已经开始确定外周组织中脂毒性的潜在机制，但对大脑中过量脂质的影响知之甚少。为了确定这些机制，我们使用了永生化的克隆下丘脑细胞系mHy-poE-44，以证明棕榈酸酯通过增加Bmal 1和Clock，或通过降低Per 2和Rev-erb α，其mRNA水平并改变其在单个神经元内的节律周期，直接改变分子时钟组件的表达。我们发现这些神经元内源性表达食欲神经肽NPY和AgRP，因此我们确定棕榈酸酯给药也改变了这些神经肽的mRNA表达。棕榈酸处理导致NPY mRNA水平显著增加，并显著改变节律表达的相位。我们使用AMPK抑制剂化合物C和AMP类似物AICAR探索AMPK和神经肽Y表达之间的联系。AMPK抑制可降低NPY mRNA的表达。AICAR也升高了基础NPY，但阻止了棕榈酸介导的NPY mRNA水平的增加。我们推测，这种棕榈酸介导的NPY和AgRP合成的增加可能会启动一个有害的正反馈回路，导致能量消耗增加。(C)2011 Elsevier Inc. All rights reserved.
The control of energy homeostasis within the hypothalamus is under the regulated control of homeostatic hormones, nutrients and the expression of neuropeptides that alter feeding behavior. Elevated levels of palmitate, a predominant saturated fatty acid in diet and fatty acid biosynthesis, alter cellular function. For instance, a key mechanism involved in the development of insulin resistance is lipotoxicity, through increased circulating saturated fatty acids. Although many studies have begun to determine the underlying mechanisms of lipotoxicity in peripheral tissues, little is known about the effects of excess lipids in the brain. To determine these mechanisms we used an immortalized, clonal, hypothalamic cell line, mHy-poE-44, to demonstrate that palmitate directly alters the expression of molecular clock components, by increasing Bmal1 and Clock, or by decreasing Per2, and Rev-erb alpha, their mRNA levels and altering their rhythmic period within individual neurons. We found that these neurons endogenously express the orexigenic neuropeptides NPY and AgRP, thus we determined that palmitate administration alters the mRNA expression of these neuropeptides as well. Palmitate treatment causes a significant increase in NPY mRNA levels and significantly alters the phase of rhythmic expression. We explored the link between AMPK and the expression of neuropeptide Y using the AMPK inhibitor compound C and the AMP analog AICAR. AMPK inhibition decreased NPY mRNA. AICAR also elevated basal NPY, but prevented the palmitate-mediated increase in NPY mRNA levels. We postulate that this palmitate-mediated increase in NPY and AgRP synthesis may initiate a detrimental positive feedback loop leading to increased energy consumption. (C) 2011 Elsevier Inc. All rights reserved.