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

自1980年以来，肥胖症和相关疾病，如高血压、血脂异常、冠状动脉疾病和糖尿病增加了一倍多，现已明确确定为发展中国家和发达国家的世界性流行病。尽管一些遗传位点被明确鉴定为肥胖的单基因原因并被广泛研究，但人们普遍认为代谢综合征本质上是一种多因素疾病，其包含分子、细胞和生理改变的复杂网络。能量平衡是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的离散神经回路进行整合，这反过来又提供了自适应的行为，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，直接调节进食和新陈代谢。下丘脑神经元的活动紧密依赖于由特定的胶质细胞亚群（星形胶质细胞）提供足够的能量底物。星形胶质细胞在大脑中非常丰富，但有时，它们只是最近才成为大脑突触可塑性的重要调节因子。星形胶质细胞急性调节神经元的氧和营养供应，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（例如，瘦素、胰岛素），并直接受到营养过剩和肥胖的影响。尽管有这些观察结果，但尚未探讨下丘脑星形胶质细胞在生理和病理生理条件下是否在能量平衡的中枢调节中发挥积极作用。在这里聚集的财团已经收集了强有力的证据，表明星形胶质细胞能够对能量相关信号做出反应，并在能量稳态中发挥重要作用。该联盟将利用合作伙伴2开发和掌握的尖端遗传工具，选择性地监测和调节体外或体内星形胶质细胞的活性。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，以识别和敲低星形胶质细胞特异性靶标。合作伙伴1将专门探索对代谢效率、胰岛素敏感性和葡萄糖代谢的影响。本项目的主要目标有两个：目的1-确定高脂饮食/肥胖过程中下丘脑星形胶质细胞的特异性分子和功能特征目的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成果是：1-更好地了解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.