Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender
Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender
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DOI：
10.1096/fj.09-150672
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发表时间：
2010-08-01
期刊：
影响因子：
4.8
通讯作者：
Lopez, Miguel
中科院分区：
文献类型：
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作者：
Lage, Ricardo;Vazquez, Maria J.;Lopez, Miguel
生长素释放肽的促食欲作用是由下丘脑弓状核 (ARC) 中的神经肽 Y (NPY) 和刺鼠相关蛋白 (AgRP) 介导的。最近的证据还表明，生长素释放肽通过一种涉及激活下丘脑 AMP 激活蛋白激酶 (AMPK) 以及灭活乙酰辅酶 A 羧化酶和脂肪酸合酶 (FAS) 的机制来促进进食。这会导致下丘脑丙二酰辅酶 A 水平降低、肉毒碱棕榈酰转移酶 1 (CPT1) 活性增加以及线粒体产生活性氧。我们评估了这些分子事件是否是独特信号级联的一部分，或者它们是否代表介导生长素释放肽促食欲作用的替代途径。此外，我们检查了这些机制的性别依赖性，因为最近的证据表明，雌性大鼠中生长素释放肽的食欲促进作用降低。我们研究了两种性别的生长素释放肽对 AgRP 和 NPY 表达的影响，以及它们的转录因子：cAMP 反应元件结合蛋白（CREB 及其磷酸化形式，pCREB）、叉头盒 O1（FoxO1 及其磷酸化形式，pFoxO1）和脑特异性同源盒转录因子（BSX）。此外，为了建立 ghrelin、脂肪酸代谢和神经肽之间的机制联系，我们使用 CPT1 抑制剂依托莫昔尔评估了 ghrelin 在阻断下丘脑脂肪酸 β 氧化后的作用。 Ghrelin 诱导的 AMPK-CPT1 通路变化与通过调节 BSX、pCREB 和 FoxO1 增加 AgRP 和 NPY mRNA 表达水平相关，以及以性别无关的方式降低内质网 (ER) 应激标记物的表达。此外，阻断下丘脑脂肪酸氧化也会阻止生长素释放肽对 AgRP 和 NPY mRNA 表达的促进作用，而且这种作用与性别无关。值得注意的是，这种效应与 BSX 表达减少和食物摄入减少有关。总体而言，我们的数据表明 BSX 以与性别无关的方式将神经元代谢状态的变化与 ARC 衍生的神经肽结合起来。-Lage, R., Vazquez, M.J., Varela, L., Saha, A. K., Vidal-Puig, A., Nogueiras, R., Dieguez, C., Lopez, M. Ghrelin 对大鼠下丘脑神经肽的影响取决于脂肪酸新陈代谢对 BSX 有影响，但对性别没有影响。 FASEB J. 24, 2670-2679 (2010)。 www.fasebj.org
The orexigenic effect of ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the hypothalamic arcuate nucleus (ARC). Recent evidence also indicates that ghrelin promotes feeding through a mechanism involving activation of hypothalamic AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase and fatty acid synthase (FAS). This results in decreased hypothalamic levels of malonyl-CoA, increased carnitine palmitoyltransferase 1 (CPT1) activity, and mitochondrial production of reactive oxygen species. We evaluated whether these molecular events are part of a unique signaling cascade or whether they represent alternative pathways mediating the orexigenic effect of ghrelin. Moreover, we examined the gender dependency of these mechanisms, because recent evidence has proposed that ghrelin orexigenic effect is reduced in female rats. We studied in both genders the effect of ghrelin on the expression of AgRP and NPY, as well as their transcription factors: cAMP response-element binding protein (CREB and its phosphorylated form, pCREB), forkhead box O1 (FoxO1 and its phosphorylated form, pFoxO1), and brain-specific homeobox transcription factor (BSX). In addition, to establish a mechanistic link between ghrelin, fatty acid metabolism, and neuropeptides, we evaluated the effect of ghrelin after blockage of hypothalamic fatty acid beta oxidation, by using the CPT1 inhibitor etomoxir. Ghrelin-induced changes in the AMPK-CPT1 pathway are associated with increased levels of AgRP and NPY mRNA expression through modulation of BSX, pCREB, and FoxO1, as well as decreased expression of endoplasmic reticulum (ER) stress markers in a gender-independent manner. In addition, blockage of hypothalamic fatty acid-oxidation prevents the ghrelin-promoting action on AgRP and NPY mRNA expression, also in a gender-independent manner. Notably, this effect is associated with decreased BSX expression and reduced food intake. Overall, our data suggest that BSX integrates changes in neuronal metabolic status with ARC-derived neuropeptides in a gender-independent manner.-Lage, R., Vazquez, M.J., Varela, L., Saha, A. K., Vidal-Puig, A., Nogueiras, R., Dieguez, C., Lopez, M. Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. FASEB J. 24, 2670-2679 (2010). www.fasebj.org