Genetic dissection of endoplasmic reticulum stress in POMC neurons

描述（由申请人提供）：肥胖已成为本世纪最紧迫的公共卫生问题之一。不幸的是，解决肥胖的高发问题被证明是极其困难的。瘦素是一种脂肪细胞衍生的激素，作用于下丘脑神经元抑制食欲和调节能量消耗，最初的发现为肥胖治疗带来了希望。然而，肥胖人群瘦素抵抗的发展阻碍了其治疗用途，这一现象的精确分子机制尚不完全清楚。有趣的是，内质网应激与肥胖有关，并与外周组织和大脑的瘦素和胰岛素抵抗有关。最近的证据表明，参与这种应激反应的一个关键部位是下丘脑。弓形POMC神经元是瘦素和胰岛素作用的关键靶点，正常的黑素皮质素信号是正常食物摄入、体重和血糖正常所必需的。因此，我们假设弓形POMC神经元参与了这种下丘脑应激反应。我们提出的实验利用Elmquist实验室和我们的合作者独特的小鼠模型来研究代谢和细胞应激在中枢瘦素和胰岛素抵抗发展中的作用。在Aim 1A中，我们将扩展我们的初步观察，并检查游离脂肪酸和其他化学刺激物对POMC神经元中瘦素和胰岛素信号传导的影响。在aim 1B中，在POMC神经元中选择性过表达XBP1s的小鼠（POMC-XBP1s）将被用来研究在这些代谢和细胞应激源刺激下，未折叠蛋白在瘦素和胰岛素信号传导中的作用。在Aim 2中，POMC-XBP1s小鼠将被用来确定增强的XBP1s信号是否可以防御饮食诱导的肥胖及其伴随的合并症。综上所述，本研究将全面测试代谢和细胞应激在POMC神经元中的作用及其对肥胖、中枢性瘦素和胰岛素抵抗发展的后续影响。

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. 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. Arcuate POMC neurons are key targets of leptin and insulin action, and normal melanocortin signaling is required for normal food intake, body weight, and euglycemia. Thus we hypothesize arcuate POMC neurons are involved in this hypothalamic stress response. The proposed experiments make use of mouse models unique to the Elmquist laboratory and our collaborators to investigate the role of metabolic and cellular stress in the development of central leptin and insulin resistance. In Aim 1A, we will extend our preliminary observations and examine the effects of free fatty acids and other chemical stimulators on leptin and insulin signaling in POMC neurons. In aim 1B, mice which selectively overexpress XBP1s in POMC neurons (POMC-XBP1s) will be used to investigate the role of the unfolded protein response in leptin and insulin signaling following stimulation by these metabolic and cellular stressors. In Aim 2, POMC-XBP1s mice will be used to determine if enhanced XBP1s signaling can defend against diet-induced obesity and accompanying co-morbidities. In summary, the proposed studies will comprehensively test the action of metabolic and cellular stress in POMC neurons and their subsequent effect on the development of obesity and central leptin and insulin resistance. PUBLIC HEALTH RELEVANCE: The proposed studies will greatly increase our understanding of the mechanisms underlying leptin and insulin resistance and obesity. The study findings will provide valuble information with which to develop treatment strategies for the prevention of obesity and diabetes.