Glial-neuronal metabolic coupling in obesity

描述(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，因为它与代谢紊乱有关，如2型糖尿病、高血压和心血管疾病。肥胖症非常普遍，影响着三分之一的美国成年人，但由于减肥势不可挡，治疗起来非常困难。由于体脂储备在瘦身和肥胖者中都受到体内平衡调节的影响，随着时间的推移，肥胖治疗的失败可能代表着对高水平的体脂质量的防御。我们最近的发现表明，控制体重的关键下丘脑区域的神经元损伤和周围胶质细胞增生是肥胖发病的重要机制。具体地说，我们观察到在啮齿动物开始高脂肪饮食期间，伴随着周围能量稳态调节神经元的细胞应激反应，反应性星形胶质细胞和小胶质细胞在下丘脑内侧基底部迅速积累。我们的K08提案侧重于下丘脑小胶质细胞在肥胖相关炎症和损伤中的作用。在这个提案中，我们扩展了这些正在进行的研究，将重点放在下丘脑星形胶质细胞和神经元之间的代谢耦合上。星形胶质细胞含有糖原储存，在突触活动增加的时候，这些糖原储存被动员起来，为周围的神经元提供乳酸。我们最近已经确定，急性阻断下丘脑星形胶质细胞糖原分解促进食物摄取，肥胖啮齿动物模型包含下丘脑星形胶质细胞糖原积累增加。这些数据支持下丘脑星形胶质细胞和神经元之间代谢偶联的破坏在肥胖发病中的作用这一前提。我们将通过确定参与食物摄入触发的乳酸利用的特定下丘脑核，饮食组成和代谢状态是否影响下丘脑乳酸的产生，以及有缺陷的星形胶质细胞糖原分解对肥胖发展的必要和充分程度来研究这一假说。从这些研究中获得的数据将为以神经胶质-神经元代谢偶联为新的肥胖靶点的新系列研究奠定基础。

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.