Cellular mechanisms governing nutrient sensing and organismal energy homeostasis

项目总结 从细菌到人类，有机体根据其自身的能力调节食物摄入量和能量消耗 体内营养状态，使他们保持健康的能量平衡。在进化过程中，保守 动态平衡机制是为了应对不断变化的食物供应带来的潜在营养匮乏而开发的。 因此，当食物充足时，多余的能量被储存为脂肪储备，并在未来短缺时被调动起来。 然而，在21世纪，营养匮乏是例外而不是常态，导致越来越多的人 肥胖在人类中的流行。肥胖影响癌症进展，加速衰老，妥协 免疫力，并阻碍健康的生活方式。我们假设对机制和分子的理解 相反的营养状态--稀缺和过剩--的界面将揭示控制关键代谢的过程 结果。此外，我们提出，某些蛋白质可以作为分子开关来控制过程。 使生物体在这两种状态下都能有效运作。我们进一步推测慢性营养过剩 削弱了“分子开关”蛋白质对营养状态作出反应的有效交替的能力， 导致能量不平衡。一旦我们确定了这样的蛋白质，我们决定将它们作为一个切入点 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 脂肪细胞是否保留或释放脂肪荷尔蒙--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 在以前的研究中，膜融合事件。然而，出乎意料的是，我们发现这种蛋白质控制着 营养状态依赖的脂肪因子在细胞内的定位和基因表达。因此，我们发现了 一种分子开关机制，在稀缺性和可塑性的交汇点控制意外的细胞过程 盈余。我们已经发现的细胞过程代表了治疗和管理的战略途径 复杂的代谢紊乱。因此，我们建议澄清以下内容：i)通过以下方式定义分子途径 这种分子开关蛋白控制着核质定位和基因表达；ii)了解 饮食诱导的肥胖如何破坏这一调节，以及iii)将这一细胞内在机制的后果映射到 生物体水平的代谢结果和行为。我们将使用果蝇来实现中短期目标，因为我们 建立了一个健壮的模拟疾病状态的果蝇生理盈余模型。我们将测试 这些发现在未来的哺乳动物系统中得到保护。总而言之，我们的目标是解决 通过采用全面和概念新颖的方法在能量生理学中解决突出问题 非常容易驯服的模型。

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.