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食性贪食和病态肥胖。静脉注射和脑室（侧脑室和第三脑室）注射瘦素都能减少食物摄入和体重，这表明瘦素通过血脑屏障作用于其在中枢神经系统中的受体，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上，但瘦素在后脑中的潜在作用却很少得到研究。为了确定后脑在调节瘦素作用中的作用，确定瘦素在脑干中的作用是直接的还是间接的是很重要的。虽然证明长形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）的激活可用于确定被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给药后脑干中soc -3的表达。接下来，将利用通道追踪方法，结合瘦素诱导基因表达的评估，建立后脑瘦素反应神经元与前脑摄食中心的连接。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。当这些神经解剖学数据与第四脑室瘦素给药的功能数据相结合时，下丘脑外部位如何参与瘦素调节能量平衡的重要作用的关键信息将被揭示。

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.