Leptin Action and Resistance in POMC-Neurons

虽然对调节能量稳态的许多因素有相当多的了解，但我们对下丘脑局部电路和这些电路背后的细胞过程的理解仍然存在空白。位于下丘脑弓状核的POMC神经元是瘦素作用的主要靶点，在调节能量稳态中起关键作用。到目前为止，关于POMC神经元的内在生理学信息有限，因为很难在脑切片或原代培养中识别它们，也很难将这些系统中的直接效应与间接效应分离出来。最近，我们的实验室开发了一种技术来鉴定和研究培养的荧光标记的POMC神经元。初步证据表明，除了表达POMC肽外，这些神经元还释放并响应GABA，这表明了一种以前未被探索的作用和

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.