NUTRIEPATHOS - NUTRIent Partitioning in Astrocytes and the regulation of energy HOmeoStasis

肥胖及其相关疾病，如高血压、血脂异常、冠心病和糖尿病，自1980年以来增加了一倍多，现在已被明确确定为发展中国家和发达国家的世界性流行病。虽然一些基因座被明确识别并被广泛研究为肥胖的单基因原因，但人们普遍认为，代谢综合征本质上是一种多因素疾病，包含了复杂的分子、细胞和生理变化网络。能量平衡源于能量消耗和营养摄入之间的微妙平衡。为了实现这一点，神经输入和循环因子通过大脑中离散的神经回路整合在一起，进而提供适应性的行为、神经内分泌和代谢反应。大脑中的下丘脑包含一个专门的神经回路，直接调节食物和新陈代谢。下丘脑神经元的活动紧密依赖于特定的神经胶质细胞亚群--星形胶质细胞--对能量底物的充分输送。星形胶质细胞在大脑中大量存在，但有时，它们只是在最近才出现，成为大脑突触可塑性的重要调节因素。星形胶质细胞敏锐地调节神经元的氧气和营养供应、神经递质的可用性和突触功能。下丘脑星形胶质细胞表达能量相关信号的大多数受体(如瘦素、胰岛素)，并直接受到营养过载和肥胖的影响。尽管有这些观察，但在生理和病理生理条件下，下丘脑星形胶质细胞是否在能量平衡的中枢调节中发挥积极作用尚不清楚。聚集在这里的财团收集了强有力的证据，表明星形胶质细胞能够对与能量相关的信号做出反应，并在能量动态平衡中发挥基础作用。该联盟将利用合作伙伴2开发和掌握的尖端基因工具，允许选择性地监测和调节星形胶质细胞的体外或体内活动。这些工具将与Partner 3开发的星形胶质细胞特异性高通量分析方法相结合，以识别和击倒星形胶质细胞特异性靶点。合作伙伴1将专门探讨对代谢效率、胰岛素敏感性和葡萄糖代谢的影响。这项提案的主要目标在于两个主要目标：目标1-定义高脂肪喂养/肥胖期间下丘脑星形胶质细胞的特定分子和功能特征目标2-利用星形胶质细胞靶向方法来治疗肥胖相关疾病。国际合作研究计划的预期结果是1-更好地了解支持下丘脑星形胶质细胞功能调节的细胞和分子机制，2-在抗肥胖、抗糖尿病治疗方面取得重大突破。

Obesity and correlated diseases such as hypertension, dyslipidemia, coronary diseases and diabetes mellitus have more than doubled since 1980 and are now clearly identified as a worldwide pandemic in both developing and developed countries. Whereas some genetic loci were clearly identified and extensively studied as monogenic causes for obesity, it is widely accepted that the metabolic syndrome is in essence a multifactorial disease that encloses a complex network of molecular, cellular and physiologic alterations. Energy homeostasis results from the exquisite balance between energy expenditure and nutrient intake. To accomplish this, nervous inputs and circulating factors are integrated by discrete neural circuits in the brain, which in turn provide an adaptive behavioral, neuroendocrine and metabolic response. The hypothalamus in the brain contains a dedicated neurocircuit that directly regulates feeding and metabolism. The activity of hypothalamic neurons is tightly dependent on adequate delivery of energy substrates by a specific subset of glial cells: the astrocytes. Astrocytes are abundant in the brain, yet at times, they have only recently emerged as a prominent regulator of brain synaptic plasticity. Astrocytes acutely regulate oxygen and nutrient supply to neurons, neurotransmitter availability and synaptic function. Hypothalamic astrocytes express most receptors for energy-related signals (e.g., leptin, insulin) and are directly affected by nutrient overload and obesity. Despite these observations it has not yet been explored whether hypothalamic astrocytes play an active role in the central regulation of energy balance under both, physiologic and pathophysiologic condition. The consortium assembled here has gathered strong evidence that astrocytes are able to respond to energy-related signals and play a fundamental role in energy homeostasis. The consortium will take advantage of cutting edge genetic tools developed and mastered by Partner 2 allowing to selectively monitor and modulate astrocyte activity either in vitro or in vivo. These tools will be combined with astrocyte-specific high-throughput analysis methods developed by Partner 3 to identify and knock-down astrocyte-specific targets. The consequences on metabolic efficiency, insulin sensitivity and glucose metabolism will be specifically explored by Partner 1. The overachieving goals of this proposal lie in 2 main aims:AIM 1-Defining the specific molecular and functional signature of hypothalamic astrocytes during high fat feeding/obesityAIM 2-Leverage astrocyte-targeted approaches to harness obesity-associated disorders.The expected outcome of the International Collaborative Research Program is 1-A better understanding on the cellular and molecular mechanism underpinning the regulation of hypothalamic astrocyte function and2- A significant breakthrough in anti-obesity, anti-diabetes therapy.