The Role of the Hindbrain in Leptin Action

描述（由申请人提供）：瘦素是一种脂肪细胞激素，向大脑发出有关外周能量储存的信号。缺乏瘦素的动物和人类是贪食和病态肥胖。静脉内和脑室内（侧脑室和第三脑室）施用瘦素都减少食物摄入和体重，这表明瘦素穿过血脑屏障作用于CNS中的其受体以发挥这些作用。虽然大多数注意力都集中在下丘脑的瘦素受体，但瘦素在后脑中的潜在作用却很少受到研究。为了确定后脑在介导瘦素作用中的作用，重要的是确定瘦素在脑干中的作用是直接的还是间接的。虽然证明长型瘦素受体在后脑中的特异性表达在技术上具有挑战性，但细胞因子信号传导抑制因子-3（SOCS-3）的激活可用于确定瘦素直接激活的后脑神经元。为了确定瘦素是否直接作用于脑干，我们将评估外周和中枢瘦素给药后脑干中的SOCS-3表达。接下来，后脑瘦素反应神经元的前脑的摄食中心的连接将建立使用束跟踪方法结合评估瘦素诱导的基因表达。我们还将描述这些瘦素反应性脑干神经元的神经化学表型和中枢投射。当这些神经解剖数据与第四心室瘦素给药的功能数据相结合时，将发现有关下丘脑外位点如何促进瘦素调节能量平衡的重要作用的关键信息。

DESCRIPTION (provided by applicant): Leptin is an adipocyte hormone that signals the brain about peripheral energy stores. Animals and humans that lack leptin are hyperphagic and morbidly obese. Both intravenous and intracerebroventricular (lateral and third ventricle) leptin administration reduce food intake and body weight demonstrating that leptin passes across the blood-brain barrier to act at its receptors in the CNS to exert these effects. While most attention has been paid to leptin receptors in the hypothalamus, the potential role of leptin action in the hindbrain has received little investigation. In order to determine the contribution of the hindbrain in mediating the effects of leptin, it is important to determine if leptin action in the brainstem is direct or indirect. While demonstration of the specific expression of the long-form leptin receptor in the hind brain has proven technically challenging, activation of suppressor of cytokine signaling-3 (SOCS-3) can be used to determine hindbrain neurons that are directly activated by leptin. To determine whether leptin acts directly in the brainstem, we will assess SOCS-3 expression in the brainstem following both peripheral and central leptin administration. Next, the connectivity of the hindbrain leptin-responsive neurons to the feeding centers of the forebrain will be established using tract tracing methods in combination with assessments of leptin-induced gene expression. We will also characterize the neurochemical phenotype and the central projections of these leptin responsive brainstem neurons. When these neuroanatomical data are combined with functional data on 4th ventricle leptin administration, critical information about how extrahypothalamic sites contribute to the important actions of leptin to regulate energy balance will be uncovered.