Hypothalamic Leptin and Insulin Signaling

描述（由申请人提供）：过去十年美国肥胖患病率显着增加，对公共健康造成严重影响。 尽管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量和体重，但尽管胰岛素和瘦素血浆浓度升高，肥胖动物和人类仍表现出高水平的食物摄入量，这表明下丘脑对这些因素的抵抗力，尽管血浆胰岛素和瘦素浓度升高，表明下丘脑对这些因素的抵抗力。 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 I3HH 和 IHC 来鉴定下丘脑内 NPY、POMC 以及 PI3K 亚基 p85 和 p110 的 PI3K 表达模式。 我们还建议使用双标记 IHC 来识别因胰岛素和瘦素治疗而出现 P13K 活性的神经元群。 最后，我们将开发针对 POMC 和 NPY 神经元的 p85 缺失的小鼠，以确定这些途径中 PI3K 信号传导对体重调节的重要性。 对这种共享的细胞内途径的深入了解将有助于治疗肥胖者瘦素受损和胰岛素调节体重。

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.