Hypothalamic PI3K signaling in regulation of energy balance & glucose homeostasis

描述(申请人提供)：瘦素和胰岛素通过将丰富的外周能量储存输送到大脑来调节能量平衡。此外，瘦素和胰岛素还作用于下丘脑，调节全身胰岛素敏感性和血糖稳态，瘦素和胰岛素的这一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。我们先前已经证明，瘦素和胰岛素直接刺激下丘脑中关键的瘦素和胰岛素靶神经元中的PI3K信号。虽然PI3K信号对胰岛素的代谢作用很重要，但最近的药理学研究表明，PI3K信号通路在介导瘦素对血糖稳态的影响中发挥了重要作用。到目前为止，仍然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要求。此外，对这种调节重要的神经元亚群还没有被识别出来。在这个方案中，我们将检验瘦素反应神经元中的PI3K是维持能量平衡和葡萄糖稳态所必需的假说。我们将确定特定瘦素反应神经元的慢性或急性PI3K基因敲除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，这两个神经元是下丘脑中两个关键的瘦素和胰岛素靶细胞。这项拟议的研究将阐明PI3K在调节能量平衡和葡萄糖动态平衡方面的功能必要性，并将确定在这一过程中重要的神经元亚群。这将促进我们对瘦素和胰岛素调节能量平衡和血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洞察力。

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.