Glial-neuronal metabolic coupling in obesity

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，因为它与代谢紊乱（如2型糖尿病、高血压和心血管疾病）有关。肥胖非常普遍，影响了1/3的美国成年人，但由于体重不可避免地会反弹，治疗起来非常具有挑战性。由于身体脂肪储存在瘦和肥胖受试者中都受到体内平衡调节，随着时间的推移，肥胖治疗的失败可能代表了身体脂肪质量水平升高的防御。我们最近的研究结果表明，控制体重的下丘脑关键区域的神经元损伤和周围胶质瘤是肥胖发病的重要机制。具体来说，我们观察到在啮齿类动物高脂肪饮食开始时，反应性星形胶质细胞和小胶质细胞在中基底下丘脑迅速积累，并伴随周围能量稳态调节神经元的细胞应激反应。我们的K08提案侧重于下丘脑小胶质细胞对肥胖相关炎症和损伤的贡献。在本提案中，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偶联。星形胶质细胞含有糖原储存，在突触活动增加的时候，糖原被动员起来为周围的神经元提供乳酸。我们最近确定，下丘脑星形胶质细胞糖原溶解的急性阻断促进食物摄入，肥胖啮齿动物模型含有增加的下丘脑星形胶质细胞糖原积累。这些数据支持了下丘脑星形胶质细胞和神经元之间代谢偶联的破坏有助于肥胖发病的前提。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产生，以及有缺陷的星形胶质细胞糖原分解在多大程度上是肥胖发展的必要和充分的来研究这一假设。从这些研究中获得的数据将形成以神经胶质-神经元代谢偶联作为新型肥胖靶点为中心的新研究路线的基础。

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.