Cellular mechanisms governing nutrient sensing and organismal energy homeostasis

控制营养感应和有机体能量稳态的细胞机制

基本信息

批准号：
10673609
负责人：
Akhila Rajan
金额：
$ 42.68万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-11 至 2027-07-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY From bacteria to humans, organisms modulate their food intake and energy expenditure in accordance with their internal nutrient state, allowing them to maintain a healthy energy balance. During evolution, conserved homeostatic mechanisms developed to cope with potential nutrient deprivation from a fluctuating food supply. Hence, when food is plentiful, excess energy is stored as fat reserves and mobilized during future scarcity. However, in the 21st-century nutritional scarcity is the exception rather than the norm, resulting in an increasing prevalence of obesity in humans. Obesity impacts cancer progression, accelerates aging, compromises immunity, and impedes a healthy lifestyle. We posited that understanding mechanisms and molecules at the interface of opposing nutrient states — scarcity and surplus — will reveal processes that control critical metabolic outcomes. Furthermore, we proposed that certain proteins function as molecular switches to control processes that allow an organism to operate in both states efficiently. We further surmised that chronic nutrient surplus impairs the capacity of the ‘molecular switch’ proteins to efficiently alternate in response to the nutritional state, resulting in energy imbalance. Once we identified such proteins, we determined to use them as an entry point to identify cellular mechanisms critical to healthy energy balance. To this end, we investigated one process: how do fat cells retain or release fat hormones – called adipokines— that serve as systemic nutrient surplus signals? Our investigations led to identifying one critical molecular switch, which is recognized as playing a role in membrane fusion events in previous studies. However, unexpectedly, we identified that this protein controls nutrient-state-dependent adipokine intracellular localization and gene expression. Therefore, we have uncovered a molecular switch mechanism that controls unanticipated cellular processes at the intersection of scarcity and surplus. The cellular processes that we have uncovered represent strategic avenues to treat and manage complex metabolic disorders. Hence, we propose to elucidate the following: i) define the molecular pathway by which this molecular switch protein controls nucleocytoplasmic localization and gene expression; ii) understand how diet-induced obesity disrupts this regulation, and iii) map consequences of this cell-intrinsic mechanism to organism-level metabolic outcomes and behaviors. We will use fruit flies for short to medium-term goals, as we have established a robust physiological Drosophila surplus model that mimics the diseased state. We will test conservations of these findings in mammalian systems in the future. In summary, our goal is to address outstanding issues in energy physiology by adopting a comprehensive and conceptually novel approach in a highly tractable model.

项目摘要从细菌到人类，生物会根据其调节食物的摄入量和能量消耗内部营养状态，使他们能够保持健康的能量平衡。在进化过程中，保守稳态机制开发出来，以应对粮食供应波动的潜在营养剥夺。因此，当食物充足时，多余的能量被存储为脂肪储备并在将来的稀缺期间动员。但是，在21世纪的营养短缺中，是例外，而不是常态人类肥胖症患病率。肥胖会影响癌症的进展，加速衰老，妥协免疫，并阻碍健康的生活方式。我们一直在了解理解机制和分子相反的营养状态的界面 - 稀缺和盈余 - 将揭示控制关键代谢的过程结果。此外，我们提出某些蛋白质充当分子开关来控制过程这使生物体在两种状态下都可以有效运行。我们进一步幸免于长期营养盈余损害“分子开关”蛋白的能力有效替代营养状态，导致能量不平衡。一旦确定了这种蛋白质，我们就决定将其用作确定对健康能量平衡至关重要的细胞机制。为此，我们调查了一个过程：脂肪细胞是否保留或释放脂肪激素（称为脂肪因子），这些脂肪因子是系统性养分剩余信号？我们的投资导致确定一个关键分子开关，该转换被认为在膜融合事件在先前的研究中。但是，出乎意料的是，我们发现该蛋白质控制营养状态依赖性脂肪因子细胞内定位和基因表达。因此，我们发现了一种分子开关机制，该机制在稀缺性和剩余。我们发现的细胞过程代表了治疗和管理的战略途径复杂的代谢障碍。因此，我们建议阐明以下内容：i）通过该分子转换蛋白控制核眼质定位和基因表达。 ii）理解饮食诱导的肥胖如何破坏这种调节，ii）将这种细胞内部机制的后果映射到有机体水平的代谢结果和行为。我们将使用水果蝇作为中期目标，因为我们已经建立了一个强大的物理果蝇盈余模型，该模型模仿了否认状态。我们将测试这些发现的保护在将来在哺乳动物系统中。总而言之，我们的目标是解决能源生理中的杰出问题通过在某种程度上采用全面且概念上的新方法高度可拖动的模型。