Nutrient fuel preference, obesity, and stem cell lineage physiology

项目总结 组织干细胞谱系维持器官功能，并对饮食和生理因素做出反应，它们 当细胞分化时，也会经历内在的代谢变化代谢/生理变化 与许多疾病有关，包括肥胖和癌症。与内在机制相关的机制 干细胞谱系中的代谢变化以及生理因素如何影响它们在很大程度上仍未得到深入研究。 果蝇卵巢是研究代谢变化及其系统调控的理想材料。 卵子发生是一个能量/营养密集型的过程，它通过 生殖系干细胞(GSC)谱系，积累脂质、碳水化合物和其他大分子。 发育受控的代谢变化发生在GSC谱系的分化过程中。在过去的时间里 ~18年来，我们的工作揭示了一个紧密协调卵子发生与整体的多器官网络- 身体生理学。GSCs及其后代在营养丰富的饮食中生长和分裂得更快，而不是在营养丰富的饮食中 脑胰岛素样肽，雷帕霉素靶标，AMP依赖激酶，类固醇激素蜕皮激素，以及 其他因素也参与了这一反应。其他器官也支持卵子发生的营养需求。为 例如，脂肪细胞脂蛋白介导的脂类运输对于卵母细胞卵黄的吸收至关重要，还有其他几种。 脂肪细胞代谢途径在卵子发生中具有特殊的作用。激素、营养素的协调， 新陈代谢，GSC谱系中高度调控的转变因此整合了来自饮食和 其他器官。然而，目前尚不清楚依赖饮食的途径如何影响细胞的新陈代谢。 沿着干细胞谱系进行分化，以及代谢紊乱(例如肥胖)如何改变这一复杂的过程。 细胞代谢与营养燃料的可获得性和利用率密切相关。主要的蜂窝燃料包括糖， 脂肪酸、氨基酸和酮体，它们的可利用性取决于整体生理 以及生物体的代谢状态。在未来5年，我们将重点解决两个主要问题 果蝇模型：1)当GSC子代发育到不同阶段时，燃料偏好如何变化 分化和对饮食依赖的生理输入的反应？2)肥胖如何影响 GSC谱系的发展、其燃料偏好和对生理信号的反应？这些项目 将提供基本的新知识，以显著推进我们对 体内干细胞谱系控制中的新陈代谢和生理学，有可能为未来提供信息 研究更多的干细胞系统以及它们的代谢去调控如何与疾病状态联系在一起。

PROJECT SUMMARY Tissue stem cell lineages maintain organ function and respond to dietary and physiological factors, and they also experience intrinsic metabolic shifts as cells differentiate Metabolic/physiological alterations are also linked to a number of diseases, including obesity and cancer. The mechanisms associated with intrinsic metabolic shifts in stem cell lineages and how physiological factors affect them remain largely underexplored. The Drosophila melanogaster ovary is ideal for the study of metabolic changes and their systemic control. Oogenesis is an energy/nutrient-intensive process that precisely links oocyte development through the germline stem cell (GSC) lineage with accumulation of lipids, carbohydrates, and other macromolecules. Developmentally-controlled metabolic changes occur along differentiation of the GSC lineage. Over the past ~18 years, our work has shed light on a multi-organ network that tightly coordinates oogenesis with whole- body physiology. GSCs and their progeny grow and divide faster on nutrient-rich rather than poor diets, and brain insulin-like peptides, Target of Rapamycin, AMP-dependent kinase, the steroid hormone ecdysone, and other factors mediate this response. Other organs also support the nutritional demands of oogenesis. For example, adipocyte lipophorin-mediated transport of lipids is crucial for oocyte yolk uptake, and several other adipocyte metabolic pathways have specific effects in oogenesis. The coordination of hormones, nutrients, metabolism, and highly regulated transitions in the GSC lineage thus integrates information from the diet and other organs. It remains unclear, however, how diet-dependent pathways affect cellular metabolism as cells differentiate along stem cell lineages, and how metabolic disorders (e.g. obesity) alter this complex process. Cellular metabolism is closely tied to nutrient fuel availability and utilization. Major cellular fuels include sugars, fatty acids, amino acids, and ketone bodies, and their availability varies depending on the overall physiological and metabolic state of the organism. Over the next 5 years, we will focus on two major questions in the Drosophila model: 1) How does fuel preference shift as GSC daughters develop through various stages of differentiation and in response to diet-dependent physiological input? 2) How does obesity impact the development of the GSC lineage, its fuel preference, and response to physiological signals? These projects will provide fundamental new knowledge to significantly advance our understanding of the integration between metabolism and physiology in the control of stem cell lineages in vivo, with the potential to inform future research additional stem cell systems and how their metabolic deregulation is tied to diseased states.