Leptin Action and Resistance in POMC-Neurons

虽然关于调节能量平衡的许多因素都有相当多的知识，但我们对下丘脑内的局部回路以及这些回路背后的细胞过程的理解仍然存在差距。位于下丘脑弓状核的POMC神经元是瘦素作用的主要靶点，在调节能量平衡方面起着至关重要的作用。到目前为止，关于POMC神经元内在生理学的信息有限，因为在脑片或原代培养中识别它们以及在这些系统中分离直接效应和间接效应是困难的。最近，我们实验室开发了一种技术来鉴定和研究培养中分离的带有荧光标记的POMC神经元。初步证据表明，除了表达POMC多肽外，这些神经元还释放GABA并对其做出反应，这表明了一种以前未被探索的作用 POMC神经元的结节。除了研究POMC神经元的GABA能性质外，本提案的目的还旨在1)研究瘦素、α-MSH、β-内啡肽和NPY对POMC神经元突触前和突触后的影响2)表征阿片3n POMC神经元的作用，并确定POMC神经元是否对阿片类药物脱敏3)确定POMC神经元中POMC多肽NPY之间是否发生相互作用以调节其活动，以及4)确定POMC神经元中是否存在瘦素受体的急性脱敏。 了解这些神经元的生理学和Lhese神经元中瘦素抵抗的细胞后果将进一步加深对下丘脑控制能量平衡的基本理解，并可能确定未来治疗肥胖症的潜在部位。

While there is considerable knowledge about many factors involved in regulating energy homeostasis, a gap remains in our understanding of local circuitry within the hypothalamus and in the cellular processes underlying these circuits. POMC neurons located in the arcuate nucleus of the hypothalamus are a major target for leptin action, and play a crucial role in regulating energy homeostasis. Thus far there is only limited information about the intrinsic physiology of POMC neurons because of the difficulties in identifying them in brain slices or primary cultures and isolating direct effects from indirect effects in these systems. Recently, our laboratory has developed a technique to identify and study isolated fluorescently abeled POMC neurons in culture. Preliminary evidence shows that in addition to expressing POMC peptides, these neurons also release and respond to GABA indicating a previously unexplored action and "nodulation of POMC neurons. In addition to studying the GABAergic nature of POMC neurons, the aims in the current proposal are also designed to 1) address the pre- and post-synaptic effects of leptin, alpha-MSH, beta-endorphin, and NPY directly on POMC neurons 2) characterize the actions of opioids 3n POMC neurons and to determine whether POMC neurons desensitize to opioids 3) determine whether interactions between POMC peptides, NPY, occur at the cellular level in POMC neurons to regulate their activity and 4) to determine if there is acute desensitization of leptin receptors in POMC neurons. Understanding the physiology of these neurons and the cellular consequences of leptin resistance in Lhese neurons will further the basic understanding of hypothalamic control of energy balance and perhaps identify potential sites for future therapeutic approaches to treat obesity.