Central Mechanisms Regulating Acute Leptin and Insulin Signaling

描述(申请人提供)：肥胖已成为本世纪最紧迫的公共卫生问题之一。不幸的是，事实证明，解决肥胖症的高发病率是极其困难的。瘦素是一种脂肪细胞衍生的激素，作用于下丘脑神经元以抑制食欲和调节能量消耗。瘦素的初步发现为肥胖治疗带来了希望。然而，它的治疗应用受到肥胖人类瘦素抵抗的发展的阻碍，这一现象的确切分子机制尚不完全清楚。同样，糖尿病的特点是胰岛素缺乏或抵抗。有趣的是，内质网(ER)应激与肥胖有关，并与周围组织和大脑中的瘦素和胰岛素抵抗有关。最近的证据 这表明参与这种应激反应的关键部位是下丘脑。值得注意的是，弓状POMC和NPY/AgRP神经元是瘦素和胰岛素作用的关键靶点。此外，正常的黑素皮质素信号对于正常的食物摄入量、体重和正常血糖是必需的。因此，我们推测弓状POMC和NPY/AgRP神经元参与了下丘脑的这种应激反应。在目前的提案中，我们将延长先前的观察结果。我们将确定内质网应激诱导急性瘦素和胰岛素抵抗的细胞机制。我们还将确定内质网应激在已确定的下丘脑神经元中调节新陈代谢的作用。

DESCRIPTION (provided by applicant): Obesity has become one of the most pressing public health issues of the current century. Unfortunately, tackling the high incidence of obesity is proving to be extremely difficult. The initial discovery of leptin, an adipocyte-derived hormone that acts on hypothalamic neurons to suppress appetite and regulate energy expenditure, raised hope for an obesity therapy. However, its therapeutic use is hampered by the development of leptin resistance in obese humans, a phenomenon for which the precise molecular mechanisms are not fully understood. Similarly, diabetes mellitus is characterized by insulin deficiency or resistance. Interestingly, endoplasmic reticulum (ER) stress is associated with obesity and implicated in leptin and insulin resistance in peripheral tissues and in the brain. Recent evidence suggests that a key site involved this stress response is the hypothalamus. Notably, arcuate POMC and NPY/AgRP neurons are key targets of leptin and insulin action. Moreover, normal melanocortin signaling is required for normal food intake, body weight, and euglycemia. Thus we hypothesize arcuate POMC and NPY/AgRP neurons are involved in this hypothalamic stress response. In the current proposal, we will extend prior observations. We will identify cellular mechanisms through which ER stress induces acute leptin and insulin resistance. We will also determine a role for ER stress in identified hypothalamic neurons to regulate metabolism.