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活化蛋白激酶（AMPK）的活性，AMPK是一种“代谢主开关”和燃料传感器。当前提案的总体目标是了解下丘脑AMPK通路在调节瘦素对能量稳态的影响中的作用。我们最近的数据表明，瘦素和其他厌氧性激素和营养物质抑制特定下丘脑核的AMPK活性，而厌氧肽激活它。在Aim 1中，我们将研究下丘脑AMPK在瘦素对食物摄入和能量平衡的影响中的作用，以及该途径的失调是否可能是一种机制

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.