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，瘦素和胰岛素也在下丘脑中起作用，调节全身胰岛素敏感性和葡萄糖稳态，瘦素和胰岛素的这种功能似乎独立于它们对摄食和肥胖的影响。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。我们之前已经证明瘦素和胰岛素直接刺激下丘脑关键瘦素和胰岛素靶神经元中的PI3K信号。虽然PI3K信号通路对胰岛素的代谢作用很重要，但最近的药理学研究表明，PI3K信号通路在调节瘦素对葡萄糖稳态的影响中起重要作用。迄今为止，仍缺乏遗传学证据来确定下丘脑PI3K信号在体内能量平衡和葡萄糖稳态中的功能需求。此外，对这种调节起重要作用的神经元亚群尚未被确定。在本提案中，我们将验证瘦素反应神经元中PI3K对于能量平衡和葡萄糖稳态的适当维持所必需的假设。我们将确定特异性瘦素反应神经元中PI3K的慢性或急性敲低是否会导致能量平衡改变、全身胰岛素抵抗增加和葡萄糖稳态受损。我们还将评估PI3K和Jak-Stat3信号在Pomc和Agrp神经元中的功能，Pomc和Agrp神经元是下丘脑中两个关键的瘦素和胰岛素靶神经元。该研究将阐明PI3K在调节能量平衡和葡萄糖稳态中的功能必要性，并将确定在这一过程中重要的神经元亚群。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机制的理解，并为肥胖和2型糖尿病的病因提供见解。

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.