Hypothalamic PI3K signaling in regulation of energy balance & glucose homeostasis

描述（由申请人提供）：瘦素和胰岛素通过向大脑输送丰富的外周能量储存来调节能量平衡。此外，瘦素和胰岛素还在下丘脑中起作用以调节全身胰岛素敏感性和葡萄糖稳态，并且瘦素和胰岛素的这种功能似乎与它们对进食和肥胖的影响无关。我们的长期目标是了解瘦素和胰岛素调节各种生理过程的信号机制。我们以前已经证明，瘦素和胰岛素直接刺激PI 3 K信号在关键瘦素和胰岛素靶神经元在下丘脑。虽然PI 3 K信号传导对于胰岛素的代谢作用是重要的，但是最近的药理学研究表明PI 3 K信号传导途径在介导瘦素对葡萄糖稳态的作用中起重要作用。迄今为止，仍然缺乏遗传证据来确定下丘脑PI 3 K信号传导在体内能量平衡和葡萄糖稳态中的功能需求。此外，神经元亚组的重要性，这种调节尚未确定。在这个建议中，我们将测试的假设，PI 3 K在瘦素反应神经元所需的能量平衡和葡萄糖稳态的适当维护。我们将确定是否慢性或急性PI 3 K敲低特定瘦素反应神经元导致改变能量平衡，增加全身胰岛素抵抗和受损的葡萄糖稳态。我们还将评估Pomc和Agrp神经元中PI 3 K和Jak-Stat 3信号传导的功能，Pomc和Agrp神经元是下丘脑中两个关键的瘦素和胰岛素靶向神经元。拟议的研究将阐明PI 3 K在介导能量平衡和葡萄糖稳态中的功能必要性，并将确定对该过程重要的神经元亚组。它将促进我们对瘦素和胰岛素调节能量平衡和葡萄糖稳态的信号传导机制的理解，并为肥胖和2型糖尿病的病因学提供见解。

DESCRIPTION (provided by applicant): Leptin and insulin regulate energy balance by conveying the abundance of peripheral energy stores to the brain. In addition, leptin and insulin also act in the hypothalamus to regulate systemic insulin sensitivity and glucose homeostasis, and this function of leptin and insulin appears to be independent of their effects on feeding and adiposity. Our long-term objective is to understand the signaling mechanisms by which leptin and insulin regulate various physiologic processes. We have previously demonstrated that leptin and insulin directly stimulate PI3K signaling in key leptin and insulin target neurons in the hypothalamus. While PI3K signaling is important for insulin's metabolic effects, recent pharmacological studies indicate that the PI3K signaling pathway plays an important role in mediating leptin's effect on glucose homeostasis. To date, genetic evidence is still lacking to establish the functional requirement of hypothalamic PI3K signaling in energy balance and glucose homeostasis in vivo. Moreover, neuronal subgroups important for this regulation have not been identified. In this proposal, we will test the hypothesis that PI3K in leptin responsive neurons is required for proper maintenance of energy balance and glucose homeostasis. We will determine whether chronic or acute PI3K knockdown in specific leptin responsive neurons leads to altered energy balance, increased systemic insulin resistance and impaired glucose homeostasis. We will also evaluate the function of PI3K and Jak-Stat3 signaling in Pomc and Agrp neurons, two key leptin and insulin target neurons in the hypothalamus. The proposed study will elucidate the functional necessity of PI3K in mediating energy balance and glucose homeostasis, and will identify the neuronal subgroups that are important for this process. It will advance our understanding of the signaling mechanisms by which leptin and insulin regulate energy balance and glucose homeostasis, and provide insight into the etiology of obesity and type 2 diabetes.