Divergent neuronal circuitries underlying acute orexigenic effects of peripheral or central ghrelin: critical role of brain accessibility.
Divergent neuronal circuitries underlying acute orexigenic effects of peripheral or central ghrelin: critical role of brain accessibility.
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DOI：
10.1111/jne.12168
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发表时间：
2014-08
影响因子：
3.2
通讯作者：
Perello M
中科院分区：
文献类型：
--
作者：
Cabral A;Valdivia S;Fernandez G;Reynaldo M;Perello M
Ghrelin是一种辛酰化肽激素，有效且快速地增加食物摄入。生长素释放肽的促食欲作用涉及下丘脑弓状核（ARC），其可接近血浆生长素释放肽并表达高水平的生长素释放肽受体。在各种其他脑核团中局部施用ghrelin也增加食物摄入。然而，目前尚不清楚这些非ARC生长素释放肽脑靶点是否受到血浆生长素释放肽生理性增加的影响。因此，目前的研究旨在阐明哪些ghrelin脑靶点参与ghrelin的短期食欲活动。首先，分析c-Fos向用生长素释放肽中枢或外周处理的小鼠脑中的诱导。已证实，外周施用的ghrelin剂量依赖性地增加食物摄入，并且主要激活ARC神经元中的c-Fos。相比之下，中枢给药的ghrelin激活大量脑核中的c-Fos。为了确定哪些细胞核可直接接近生长素释放肽，向小鼠中枢或外周注射荧光生长素释放肽示踪剂。结果发现，外周注射的示踪剂主要进入ARC，而中枢注射的示踪剂到达已知表达ghrelin受体的大多数脑区。随后，测试ARC消融小鼠中的生长素释放肽作用，发现这些小鼠未能响应于外周施用的生长素释放肽而增加食物摄入，但对中枢施用的生长素释放肽完全响应。ARC消融小鼠表现出类似的模式ghrelin诱导的c-Fos的表达，在对照组小鼠中所看到的，除了ARC，在那里没有c-Fos被发现。中枢ghrelin进入多种细胞核，即使在没有完整ARC的情况下，这些细胞核也可以介导激素的促食欲作用。
Ghrelin is an octanoylated peptide hormone that potently and rapidly increases food intake. The orexigenic action of ghrelin involves the hypothalamic arcuate nucleus (ARC), which is accessible to plasma ghrelin and expresses high levels of the ghrelin receptor. Local administration of ghrelin in a variety of other brain nuclei also increases food intake. It is currently unclear, however, if these non-ARC ghrelin brain targets are impacted by physiological increases of plasma ghrelin. Thus, the current study was designed to clarify which ghrelin brain targets participate in the short-term orexigenic actions of ghrelin. First, c-Fos induction into mouse brains centrally or peripherally treated with ghrelin was analyzed. It was confirmed that peripherally administered ghrelin dose dependently increases food intake and mainly activates c-Fos in ARC neurons. In contrast, centrally administered ghrelin activates c-Fos in a larger number of brain nuclei. To determine which nuclei are directly accessible to ghrelin, mice were centrally or peripherally injected with a fluorescent ghrelin tracer. It was found that peripherally injected tracer mainly accesses the ARC while centrally injected tracer reaches most brain areas known to express ghrelin receptors. Following that, ghrelin effects in ARC-ablated mice were tested and it was found that these mice failed to increase food intake in response to peripherally administered ghrelin but fully responded to centrally administered ghrelin. ARC-ablated mice showed similar patterns of ghrelin-induced c-Fos expression as seen in control mice with the exception of the ARC, where no c-Fos was found. Thus, peripheral ghrelin mainly accesses the ARC, which is required for the orexigenic effects of the hormone. Central ghrelin accesses a variety of nuclei, which can mediate the orexigenic effects of the hormone even in the absence of an intact ARC.
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