Hypothalamic Leptin and Insulin Signaling

描述（由申请人提供）：在过去的十年中，美国肥胖症患病率的显著增加对公共健康构成了严重威胁。 虽然循环肥胖信号瘦素和胰岛素可以减少动物模型中的食物摄入和体重，但肥胖动物和人表现出高水平的食物摄入，尽管胰岛素和瘦素的血浆浓度升高，表明下丘脑对这些的抗性，尽管胰岛素和瘦素的血浆浓度升高，表明下丘脑对这些因子的抗性。 我们的研究旨在确定PI3K通路对下丘脑内关键神经元亚群中胰岛素和瘦素信号传导的重要性。 我们建议使用双标记的I3HH和免疫组化的NPY，POMC，和PI3K亚基p85和p110的下丘脑内的PI3K的表达模式。 我们还建议使用双标记的免疫组化，以确定神经元群体中发生的P13 K活性在胰岛素和瘦素治疗。 最后，我们将开发针对POMC和NPY神经元的p85缺失小鼠，以确定PI3K信号传导在这些途径中对体重调节的重要性。 深入了解这一共同的细胞内途径将有助于治疗肥胖患者中受损的瘦素和胰岛素对体重的调节。

DESCRIPTION (provided by applicant): The marked increase in the prevalence of obesity in the Untied States over the past decade poses a serious thereat to public health. Although the circulating adiposity signals leptin and insulin can reduce food intake and body weights in animal models, obese animals and humans exhibit high levels of food intake despite elevated plasma concentrations of insulin and leptin, indicating hypothalamic resistance to these despite elevated plasma concentrations of insulin and leptin, indicating hypothalamic resistance to these factors. Our research seeks to determine the importance of the PI3K pathway to insulin and leptin signaling in crucial neuronal subgroups within the hypothalamus. We propose to identity the expression pattern of PI3K within the hypothalamus using double-labeled I3HH and IHC for NPY, POMC, and the PI3K subunits p85 and p110. We also propose to use double-labeled IHC to identify neuronal populations in which P13K activity occurs in response to insulin and leptin treatment. Finally, we will develop mice with deletions of p85 targeted to POMC and NPY neurons to determine the importance of PI3K signaling in these pathways to the regulation of body weight. Insight into this shared intracellular pathway will allow progress toward treatment of impaired leptin and insulin regulation of body weight in the obese.