Hypothalamic Leptin and Insulin Signaling

描述(申请人提供)：在过去的十年里，美国肥胖率的显著上升对公众健康构成了严重的威胁。尽管在动物模型中，循环肥胖信号瘦素和胰岛素可以减少食物摄入量和体重，但肥胖动物和人类表现出高水平的食物摄入量，尽管血浆胰岛素和瘦素浓度升高，但表明下丘脑对这些因素具有抵抗力，表明下丘脑对这些因素具有抵抗力。我们的研究试图确定PI3K通路在下丘脑内关键神经元亚群中对胰岛素和瘦素信号的重要性。我们建议使用NPY、POMC以及PI3K亚单位P85和P110的I3HH和IHC双标记来鉴定PI3K在下丘脑中的表达模式。我们还建议使用双标记IHC来识别在胰岛素和瘦素治疗中发生P13K活性的神经元群体。最后，我们将建立针对POMC和NPY神经元的P85缺失的小鼠，以确定这些通路中的PI3K信号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肥胖者瘦素受损的治疗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.