Hypothalamic Leptin and Insulin Signaling

描述（由申请人提供）：在过去十年中，美国肥胖患病率的显著增加对公众健康构成了严重威胁。尽管在动物模型中，循环脂肪信号瘦素和胰岛素可以减少食物摄入量和体重，但肥胖动物和人类在血浆胰岛素和瘦素浓度升高的情况下仍表现出高水平的食物摄入量，这表明尽管血浆胰岛素和瘦素浓度升高，下丘脑对这些因素有抵抗，这表明下丘脑对这些因素有抵抗。我们的研究旨在确定PI3K通路对下丘脑关键神经元亚群中胰岛素和瘦素信号的重要性。我们建议使用双标记I3HH和IHC来识别NPY、POMC和PI3K亚基p85和p110在下丘脑中的表达模式。我们还建议使用双标记免疫组化来识别P13K活性在胰岛素和瘦素治疗下发生的神经元群体。最后，我们将培养针对POMC和NPY神经元的p85缺失小鼠，以确定这些途径中PI3K信号传导对体重调节的重要性。深入了解这种共享的细胞内通路将有助于治疗肥胖患者的瘦素和胰岛素调节体重受损。

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.