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.

项目概要从细菌到人类，生物体根据自身的情况调节食物摄入和能量消耗内部营养状态，使它们在进化过程中保持健康的能量平衡。体内平衡机制的发展是为了应对食物供应波动造成的潜在营养匮乏。因此，当食物充足时，多余的能量会作为脂肪储备储存起来，并在未来食物短缺时动员起来。然而，在 21 世纪，营养匮乏只是例外而非常态，导致营养匮乏的情况日益严重。肥胖在人类中的流行会影响癌症的进展、加速衰老、损害健康。免疫力，并阻碍健康的生活方式。我们假设了解机制和分子。竞争营养状态（稀缺和过剩）的界面将揭示控制关键代谢的过程此外，我们提出某些蛋白质充当分子开关来控制过程。使有机体能够在两种状态下有效运作，我们进一步推测长期营养过剩。损害“分子开关”蛋白质有效地响应营养状态的能力，一旦我们识别出此类蛋白质，我们就决定将它们用作能量失衡的切入点。确定对健康能量平衡至关重要的细胞机制为此，我们研究了一个过程：如何进行。脂肪细胞是否保留或释放脂肪激素（称为脂肪因子）作为全身营养过剩信号？我们的研究发现了一个关键的分子开关，它被认为在然而，出乎意料的是，我们发现该蛋白控制着之前的研究中的膜融合事件。因此，我们发现了营养状态依赖性脂肪因子的细胞内定位和基因表达。一种分子开关机制，可在稀缺性和稀缺性交汇处控制意外的细胞过程我们发现的细胞过程代表了治疗和管理过剩的战略途径。因此，我们建议阐明以下内容：i）通过以下方式定义分子途径。该分子开关蛋白控制核细胞质定位和基因表达 ii) 了解；饮食引起的肥胖如何破坏这种调节，以及 iii) 将这种细胞内在机制的后果映射到我们将利用果蝇来实现短期到中期的目标，就像我们一样。已经建立了一个强大的生理果蝇剩余模型来模拟患病状态我们将进行测试。总之，我们的目标是解决未来在哺乳动物系统中保存这些发现的问题。通过采用全面且概念新颖的方法来解决能量生理学中的突出问题高度易处理的模型。