CENTRAL AND PERIPHERAL TARGETS FOR METABOLIC ACTIONS OF LEPTIN

了解瘦素信号对于了解体重调节至关重要。我们发现，瘦素调节AMP激活的蛋白激酶(AMPK)的活性，AMPK是“代谢总开关”和燃料传感器。目前这项研究的总体目标是了解下丘脑AMPK通路在调节瘦素对能量平衡的影响中所起的作用。我们最近的数据表明，瘦素和其他厌氧激素和营养素抑制特定下丘脑核团中的AMPK活性，而促食欲素多肽则激活它。在目标1中，我们将研究下丘脑AMPK在瘦素影响食物摄取和能量平衡中的作用，以及这一途径的异常是否可能是 瘦素抵抗。我们将确定未能抑制AMPK活性对Leptjn的反应是否会导致Leptin抵抗，这是饮食诱导肥胖的特征。在目标2中，我们将确定下丘脑AMPK通路如何与其他瘦素信号通路(STAT3和PIS激酶)在调节食物摄入量和体重方面相结合。在目标3中，我们将通过免疫组织化学和转基因方法结合Aderio相关病毒载体在特定神经元中表达显性阴性和结构性活性的AMPK来确定介导AMPK对食物摄入量和能量稳态影响的神经通路。在目标4中，我们将确定瘦素对下丘脑室旁核AMPK活性的影响是直接的还是间接的，是通过弓状核的神经元。我们还将确定仅在PVH中改变AMPK活性是否足以改变食物摄入量和能量平衡。这些研究将提供对信令电路的关键见解 调节荷尔蒙和营养调节能量平衡。

Understanding leptin signaling is essential for understanding body weight regulation. We discovered that leptin regulates the activity of the AMP-activated protein kinase (AMPK), a "metabolic master switch" and a fuel sensor. The overall goal of the current proposal is to understand the role of the AMPK pathway in the hypothalamus in mediating leptin's effects on energy homeostasis. Our data recent show that leptin and other anorexigenic hormones and nutrients inhibit AMPK activity in specific hypothalamic nuclei and orexigenic peptides activate it. In Aim 1 we will investigate the role of hypothalamic AMPK in leptin's effect on food intake and energy balance and whether dysregulatibn of this pathway could be a mechanism for leptin resistance. We will determine whether failure to inhibit AMPK activity in response to leptjn contributes to the leptin resistance that is characteristic of diet-induced obesity. In Aim 2 we will determine how the hypothalamic AMPK pathway integrates with other leptin signaling pathways (STAT3 and PIS kinase) in regulating food intake and body weight. In Aim 3 we will determine the neuronal pathways mediating the effects of AMPK on food intake and energy homeostasis using immunohistochemistry and expression of dominant negative and constitutively active AMPK in specific neurons using transgenic approaches combined with aderio associated viral vectors. In Aim 4 we will determine whether the effect of leptin on AMPK activity in the paraventricular hypothalamus is direct or indirect through neurons in the arcuate nucleus. We will also determine whether altering AMPK activity only in the PVH is sufficient to alter food intake and energy homeostasis. These studies will provide critical insights into the signaling circuits that mediate hormonal and nutrient regulation of energy balance.