Glycophagy in liver and skeletal muscle insulin sensitivity and energy metabolism

项目总结/摘要 肝脏和骨骼肌胰岛素抵抗是2型糖尿病患者的两个核心缺陷。 虽然糖原代谢失调与胰岛素敏感性有关，但其机制尚不完全清楚。 糖原代谢改变胰岛素敏感性。申请人生成的新的初步数据表明， 溶酶体酶α-酸性葡糖苷酶对糖原的自噬降解（即糖噬） (GAA)在调节肝脏和骨骼胰岛素敏感性和能量方面起着以前未被认识的作用 新陈代谢.在小鼠中，高脂肪饮食喂养降低了胰岛素敏感性，这种效应与胰岛素敏感性增加有关。 肝脏GAA水平，而运动或肌肉收缩增加胰岛素敏感性， 降低肌肉GAA水平。在肝脏或骨骼肌细胞中进行的后续机制研究表明， 抑制糖噬作用降低了糖酵解能力，同时增加了胰岛素敏感性，线粒体生物发生， 和脂肪酸氧化，这些作用与SIRT 1信号的诱导和减少氧化有关。 应力为了更好地确定小鼠的糖噬、胰岛素敏感性和能量代谢之间的联系， 申请人使用CRISPR/Cas 9技术来产生具有可诱导的肝脏或骨骼的新型小鼠模型， GAA的肌肉特异性敲除。本K 01提案的总体目标是确定以下方面的作用： 小鼠肝脏和骨骼肌中的糖吞噬、胰岛素敏感性和能量代谢。另夕h 申请人已组成跨学科赠款咨询小组，为 提议的研究。培训计划的目的是建立在申请人以前的专业知识在新陈代谢 通过提供分析技术、研究概念、数据分析、赠款和手稿方面的额外培训 写作、示踪方法的教学培训、建立富有成效的合作和领导技能。这 该提案将帮助申请人在糖噬领域启动自己的研究利基，并作为一个 他独立研究生涯的跳板

Project Summary / Abstract Liver and skeletal muscle insulin resistance represent two core defects in individuals with Type 2 Diabetes. Although dysregulated glycogen metabolism is linked to insulin sensitivity, it is not entirely understood how glycogen metabolism modifies insulin sensitivity. New preliminary data generated by the applicant suggests that the autophagic degradation of glycogen (i.e. glycophagy) by the lysosomal enzyme alpha acid glucosidase (GAA) plays a previously unrecognized role in modulating liver and skeletal insulin sensitivity and energy metabolism. In mice, high-fat diet feeding reduced insulin sensitivity, an effect associated with an increase in liver GAA levels, whereas exercise or muscle contraction increased insulin sensitivity, an effect associated with reduced muscle GAA levels. Follow-up mechanistic studies in liver or skeletal muscle cells showed that acute inhibition of glycophagy reduced glycolytic capacity while increasing insulin sensitivity, mitochondrial biogenesis, and fatty acid oxidation, effects that were associated with an induction of SIRT1 signaling and reduced oxidative stress. To better define the link between glycophagy, insulin sensitivity, and energy metabolism in mice, the applicant used CRISPR/Cas 9 technology to generate a novel mouse model with inducible liver or skeletal muscle specific knockout of GAA. The overarching objective of this K01 proposal is to define the role of glycophagy in liver and skeletal muscle insulin sensitivity and energy metabolism in mice. Additionally, the applicant has assembled an interdisciplinary grant advisory panel to provide mentorship and guidance for the proposed research. The training plan was designed to build upon the applicant’s prior expertise in metabolism by providing additional training in analytical techniques, research concepts, data analysis, grant and manuscript writing, didactic training in tracer methodology, establishing productive collaborations, and leadership skills. This proposal will help the applicant initiate his own investigative niche in the field of glycophagy and serve as a springboard to his independent research career.