Leptin Action and Resistance in POMC-Neurons

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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.