Glial-neuronal metabolic coupling in obesity

肥胖中的胶质神经元代谢耦合

• 批准号: 8681979
• 负责人: JOSHUA P THALER
• 金额: $ 8.7万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-20 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681979
• 关键词: Acute; Address; Adult; Affect; Area; Astrocytes; Award; Behavior; Biosensor; Body Weight; Body Weight decreased; Body fat; Brain; Brain Injuries; Carbohydrates; Cardiovascular Diseases; Cell Nucleus; Cellular Stress Response; Chronic; Complex; Conscious; Consumption; Coupling; Data; Defect; Developed Countries; Development; Diabetes Mellitus; Diet; Dorsal; Eating; Energy-Generating Resources; Equilibrium; Failure; Fatty acid glycerol esters; Feeding behaviors; Gliosis; Glycogen; Health; Homeostasis; Human; Hypertension; Hypoglycemia; Hypothalamic structure; Impairment; Implant; Inflammation; Injury; Investigation; Ischemia; Lactate Transporter; Lateral; Learning; Malignant Neoplasms; Measures; Memory; Metabolic; Metabolic Diseases; Microglia; Morbidity - disease rate; Nature; Nerve Degeneration; Neuroglia; Neuronal Injury; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Peptides; Play; Population; Pro-Opiomelanocortin; Production; Rattus; Regulation; Research; Rodent; Rodent Model; Role; Signal Transduction; Site; Surface; Synapses; Time; United States; Weight; Weight Gain; Weight maintenance regimen; base; biological adaptation to stress; extracellular; falls; feeding; food consumption; gene therapy; glycogenolysis; improved; leptin receptor; mortality; neuronal survival; novel; public health relevance; response; success; therapeutic target

DESCRIPTION (provided by applicant): Obesity is among the most challenging health problems confronting developed countries due to its association with metabolic disorders such as type 2 diabetes, hypertension, and cardiovascular disease. Obesity is remarkably common, affecting >1/3rd of US adults, but is very challenging to treat due to the inexorable regain of los weight. Since body fat stores are subject to homeostatic regulation in both lean and obese subjects, the failure of obesity therapy over time likely represents the defense of an elevated level of body fat mass. Our recent findings implicate neuron injury and surrounding gliosis in key hypothalamic areas for body weight control as a significant contributory mechanism to obesity pathogenesis. Specifically, we observed a rapid accumulation of reactive astrocytes and microglia in the mediobasal hypothalamus during the initiation of high fat diet consumption in rodents concomitant with cellular stress responses in surrounding energy homeostasis- regulating neurons. Our K08 proposal focused on the contribution of hypothalamic microglia to obesity- associated inflammation and injury. In this proposal, we extend these ongoing investigations to focus on metabolic coupling between hypothalamic astrocytes and neurons. Astrocytes contain glycogen stores that are mobilized to provide lactate to surrounding neurons during times of increased synaptic activity. We have recently determined that acute blockade of hypothalamic astrocyte glycogenolysis promotes food intake, and that obese rodent models contain increased hypothalamic accumulations of astrocyte glycogen. These data support the premise that disruption of metabolic coupling between hypothalamic astrocytes and neurons contributes to obesity pathogenesis. We will investigate this hypothesis by determining the specific hypothalamic nuclei involved in food intake-triggered lactate utilization, whether diet composition and metabolic status affect hypothalamic lactate production, and the extent to which defective astrocyte glycogenolysis is necessary and sufficient for the development of obesity. The data obtained from these investigations will form the basis of a new line of research centered on glial-neuronal metabolic coupling as a novel obesity target.

描述（由申请人提供）：肥胖是发达国家面临的最具挑战性的健康问题之一，因为它与2型糖尿病，高血压和心血管疾病等代谢疾病的关联。肥胖非常普遍，影响了美国成年人的> 1/3，但是由于LOS体重的不可避免，治疗非常具有挑战性。由于体内脂肪储存在瘦肉和肥胖受试者中都受到稳态调节，因此随着时间的流逝，肥胖治疗的失败可能代表了体内脂肪质量升高的防御。我们最近的发现暗示神经元损伤和关键下丘脑区域中的神经胶质控制，以控制体重，这是肥胖发病机理的重要促进机制。具体而言，我们观察到在啮齿类动物的高脂饮食消耗期间，在床上脂肪饮食中迅速积累了反应性星形胶质细胞和小胶质细胞，以及周围能量稳态调节神经元的细胞应激反应。我们的K08提案着重于下丘脑小胶质细胞对肥胖相关的炎症和损伤的贡献。在此提案中，我们将这些正在进行的研究扩展到下丘脑星形胶质细胞和神经元之间的代谢耦合。星形胶质细胞包含糖原储存，这些糖原储存在增加的突触活动时动员为周围神经元提供乳酸。我们最近确定，下丘脑星形胶质细胞糖基溶解的急性阻断可促进食物摄入，肥胖的啮齿动物模型含有增加的星形胶质细胞糖原下丘脑积累。这些数据支持下丘脑星形胶质细胞和神经元之间代谢耦合的破坏有助于肥胖发病机理。我们将通过确定参与食物摄取的乳酸利用的特异性下丘脑核，是否影响下丘脑乳酸的产生以及缺陷的星形胶质细胞糖原分解是必要且足以发展出肥胖的发展是必要且足够的程度。从这些研究中获得的数据将构成以神经神经神经胶质代谢耦合为中心的新研究系列的基础。