Glycophagy in liver and skeletal muscle insulin sensitivity and energy metabolism

项目摘要/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。 尽管糖原代谢失调与胰岛素敏感性有关，但人们并不完全了解它是如何 糖原代谢改变胰岛素敏感性。申请者产生的新的初步数据表明 溶酶体酶α-酸性葡萄糖苷酶对糖原的自噬降解(即糖噬作用) (GAA)在调节肝脏和骨骼的胰岛素敏感性和能量方面发挥着以前未被认识的作用。 新陈代谢。在小鼠中，高脂饮食喂养降低了胰岛素敏感性，这一效果与增加 肝脏GAA水平，而运动或肌肉收缩则增加胰岛素敏感性，这一效应与 降低肌肉GAA水平。对肝脏或骨骼肌细胞的后续机制研究表明，急性 抑制吞噬糖会降低糖酵解能力，同时增加胰岛素敏感性，线粒体生物发生， 和脂肪酸氧化，与诱导SIRT1信号和减少氧化有关的效应 压力。为了更好地确定小鼠的吞糖性、胰岛素敏感性和能量代谢之间的联系， 申请人使用CRISPR/CAS9技术建立了一种新的具有诱导肝脏或骨骼的小鼠模型 肌肉特异性GAA基因敲除。此K01提案的总体目标是定义 小鼠肝脏和骨骼肌的吞糖性、胰岛素敏感性和能量代谢。此外， 申请人已成立一个跨学科的拨款顾问团，为 拟开展的研究。培训计划是以申请者先前在新陈代谢方面的专业知识为基础设计的 提供分析技术、研究概念、数据分析、补助金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，以及领导技能。这 提案将帮助申请者在糖噬菌领域开创自己的研究利基市场，并充当 成为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.