Genetic dissection of endoplasmic reticulum stress in POMC neurons

POMC 神经元内质网应激的基因解剖

• 批准号: 8046381
• 负责人: KEVIN W WILLIAMS
• 金额: $ 11.88万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046381
• 关键词: Acute; Adipocytes; Animals; Body Weight; Brain; Cells; Cellular Stress; Central obesity; Chemicals; Comorbidity; Data; Desire for food; Development; Diabetes Mellitus; Diet; Dissection; Dithiothreitol; Eating; Embryo; Endoplasmic Reticulum; Energy Metabolism; Epidemic; Exhibits; Exposure to; Fatty acid glycerol esters; Feeding behaviors; Fibroblasts; Genes; Genetic; Homeostasis; Hormones; Human; Hyperglycemia; Hypothalamic structure; Incidence; Inflammatory; Insulin; Insulin Resistance; Insulin Signaling Pathway; Knock-out; Knowledge; Laboratories; Lead; Leptin; Leptin resistance; Link; Liver; Mediator of activation protein; Metabolic; Metabolic stress; Modeling; Molecular; Mus; Muscle; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutritional; Obesity; Overweight; Pathway interactions; Peripheral; Population; Prevalence; Proteins; Public Health; Resistance; Role; Series; Signal Transduction; Site; Slice; Stress; System; Testing; Tetanus Helper Peptide; Therapeutic Uses; Time; Tissues; Trans-Activators; Transgenic Mice; Tunicamycin; United States; Up-Regulation; Weight Gain; Work; biological adaptation to stress; blood glucose regulation; cell type; endoplasmic reticulum stress; insulin sensitivity; insulin signaling; knockout animal; mouse model; new therapeutic target; novel; obesity prevention; obesity treatment; overexpression; prevent; protein misfolding; public health relevance; receptor; research study; response; stressor; treatment strategy

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.

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，解决肥胖症的高发率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，调节能量消耗，瘦素的最初发现为肥胖治疗带来了希望。然而，它的治疗用途受到肥胖人群中瘦素抵抗的发展的阻碍，这种现象的精确分子机制尚未完全理解。有趣的是，内质网（ER）应激与肥胖有关，并与外周组织和大脑中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关键部位是下丘脑。弓状POMC神经元是瘦素和胰岛素作用的关键靶点，并且正常的黑皮质素信号传导是正常的食物摄入、体重和健康所必需的。因此，我们假设弓状POMC神经元参与下丘脑的应激反应。拟议的实验利用Elmquist实验室和我们的合作者特有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。在目标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。在目标1B中，将使用在POMC神经元中选择性过表达XBP 1的小鼠（POMC-XBP 1）来研究在这些代谢和细胞应激刺激后未折叠蛋白应答在瘦素和胰岛素信号传导中的作用。在目标2中，POMC-XBP 1 s小鼠将用于确定增强的XBP 1 s信号传导是否可以防御饮食诱导的肥胖和伴随的共病。总之，所提出的研究将全面测试POMC神经元中代谢和细胞应激的作用及其对肥胖和中枢瘦素和胰岛素抵抗的发展的后续影响。 公共卫生关系：这些研究将大大增加我们对瘦素、胰岛素抵抗和肥胖的机制的理解。研究结果将为制定预防肥胖和糖尿病的治疗策略提供有价值的信息。