Perello Mario, Stuart Ronald C, Nillni Eduardo A
Division of Endocrinology, Department of Medicine, Brown Medical School/Rhode Island Hospital, 55 Claverick Street, 4th Floor, Room 430, Providence, 02903, USA.
Endocrinology. 2006 Jul;147(7):3296-306. doi: 10.1210/en.2005-1533. Epub 2006 Apr 20.
We previously have shown that leptin regulates proTRH in the paraventricular nucleus (PVN) of the hypothalamus through two pathways. The first one acts directly on proTRH neurons, and the second one (indirect) acts through the melanocortin system (arcuate nucleus). However, it is unknown whether the direct or the indirect pathways of leptin action on proTRH neurons occurs on separated or on the same subsets of neurons within the PVN region. We used immunostaining for the phosphorylated signal transducer and activator of transcription 3 to localize direct leptin signaling, and the phosphorylated cAMP response element binding protein to localize indirect signaling on proTRH neurons in animals intracerebroventricularly injected with leptin. With this approach we were able to identify two subsets of neuronal populations responsive to leptin, which are distributed in different regions within the PVN. ProTRH neurons directly responsive to leptin were located mainly in the medial and posterior part of the PVN, and they were not primarily related to the hypothalamic pituitary thyroid axis. Whereas, proTRH neurons indirectly responsive (through alpha-MSH) to leptin were located mainly in the anterior, medial, and periventricular part of the PVN, and related to the hypothalamic pituitary thyroid axis. In addition, alpha-MSH showed to affect the processing of proTRH and up-regulated the prohormone convertase 1/3. In this study, we show evidence supporting the hypothesis that in the PVN there are subpopulations of proTRH neurons responding to leptin, which is dependent upon the way leptin reaches its primary target(s) in the hypothalamus. These findings are critical to a better understanding of leptin-mediated actions in energy expenditure.
我们之前已经表明，瘦素通过两条途径调节下丘脑室旁核（PVN）中的促甲状腺激素释放激素原（proTRH）。第一条途径直接作用于促甲状腺激素释放激素原神经元，第二条途径（间接途径）通过黑皮质素系统（弓状核）起作用。然而，瘦素作用于促甲状腺激素释放激素原神经元的直接或间接途径是发生在PVN区域内不同的神经元亚群上，还是同一亚群上，目前尚不清楚。我们使用磷酸化信号转导子和转录激活子3的免疫染色来定位瘦素的直接信号传导，并用磷酸化的环磷酸腺苷反应元件结合蛋白来定位在脑室内注射瘦素的动物中促甲状腺激素释放激素原神经元上的间接信号传导。通过这种方法，我们能够识别出对瘦素有反应的两个神经元群体亚群，它们分布在PVN内的不同区域。直接对瘦素有反应的促甲状腺激素释放激素原神经元主要位于PVN的内侧和后部，它们与下丘脑 - 垂体 - 甲状腺轴没有主要关联。而间接（通过α - 促黑素）对瘦素有反应的促甲状腺激素释放激素原神经元主要位于PVN的前部、内侧和室周部分，并且与下丘脑 - 垂体 - 甲状腺轴相关。此外，α - 促黑素显示会影响促甲状腺激素释放激素原的加工，并上调激素原转化酶1/3。在这项研究中，我们提供了证据支持以下假设：在PVN中存在对瘦素有反应的促甲状腺激素释放激素原神经元亚群，这取决于瘦素到达其在下丘脑的主要靶点的方式。这些发现对于更好地理解瘦素在能量消耗中的介导作用至关重要。
