CENTRAL AND PERIPHERAL TARGETS FOR METABOLIC ACTIONS OF LEPTIN

瘦素代谢作用的中枢和外周目标

• 批准号: 6928801
• 负责人: BARBARA B. KAHN
• 金额: $ 37.68万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928801
• 关键词: appetite; bioenergetics; eating; enzyme activity; genetically modified animals; hormone regulation /control mechanism; hypothalamus; immunocytochemistry; laboratory mouse; leptin; nutrition related tag; paraventricular nucleus; protein kinase

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.

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激活蛋白激酶（AMPK）、“代谢总开关”和燃料传感器的活性。目前建议的总体目标是了解AMPK通路在下丘脑中介导瘦素对能量稳态的影响的作用。我们最近的数据表明，瘦素和其他促食欲激素和营养素抑制下丘脑特定核团的AMPK活性，而促食欲肽激活它。目的1我们将研究下丘脑AMPK在瘦素影响食物摄入和能量平衡中的作用，以及该途径的失调是否可能是瘦素影响下丘脑能量平衡的机制。 瘦素抵抗我们将确定未能抑制AMPK活性以响应leptin是否有助于瘦素抵抗，瘦素抵抗是饮食诱导的肥胖的特征。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）整合，以调节食物摄入和体重。在目标3中，我们将使用免疫组织化学和使用转基因方法结合Aderio相关病毒载体在特定神经元中表达显性负性和组成性活性AMPK来确定介导AMPK对食物摄入和能量稳态的影响的神经元通路。在目的4中，我们将确定瘦素对室旁下丘脑AMPK活性的影响是直接的还是通过弓状核神经元间接的。我们还将确定仅改变PVH中的AMPK活性是否足以改变食物摄入和能量稳态。这些研究将提供关键的见解信号电路， 调节能量平衡的激素和营养调节。