Glycophagy in liver and skeletal muscle insulin sensitivity and energy metabolism

肝脏和骨骼肌胰岛素敏感性和能量代谢中的糖吞噬

• 批准号: 10220961
• 负责人: Timothy D. Heden
• 金额: $ 13.94万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220961
• 关键词: Acids; Acute; Antioxidants; Biochemical; Bioenergetics; Biogenesis; Biological Assay; Blood Glucose; CRISPR/Cas technology; Cells; Collaborations; Coupled; Data; Data Analyses; Defect; Development; Energy Metabolism; Enzymes; Exercise; Glucan 1,4-alpha-Glucosidase; Glucose Clamp; Glycogen; Gold; Grant; Health; Hepatic; High Fat Diet; Impairment; Indirect Calorimetry; Individual; Insulin Resistance; Knock-out; Leadership; Link; Liver; Manuscripts; Mentorship; Metabolism; Methodology; Methods; Mitochondria; Mus; Muscle; Muscle Contraction; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Organ; Oxidative Stress; Pathology; Play; Prevention; Public Health; Research; Resolution; Role; SIRT1 gene; Signal Transduction; Skeletal Muscle; Techniques; Technology; Testing; Tracer; Training; Writing; career; design; experimental study; fatty acid metabolism; fatty acid oxidation; feeding; follow-up; glucose disposal; glucose output; glucosidase; glycogen metabolism; high standard; improved; insight; insulin sensitivity; metabolomics; mitochondrial metabolism; mouse model; novel; novel therapeutic intervention; oxidation; prevent; skeletal; skills

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.

项目概要/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，但尚不完全清楚如何 申请人产生的新的初步数据表明，糖原代谢改变胰岛素敏感性。 溶酶体酶 α 酸性葡萄糖苷酶对糖原的自噬降解（即糖吞噬） (GAA) 在调节肝脏和骨骼胰岛素敏感性和能量方面发挥着以前未被认识的作用 在小鼠中，高脂肪饮食会降低胰岛素敏感性，这种效应与胰岛素敏感性增加有关。 肝脏 GAA 水平，而运动或肌肉收缩会增加胰岛素敏感性，这种效应与 肝脏或骨骼肌细胞的后续机制研究表明，肌肉 GAA 水平降低。 抑制糖吞噬会降低糖酵解能力，同时增加胰岛素敏感性、线粒体生物合成， 和脂肪酸氧化，与诱导 SIRT1 信号传导和减少氧化相关的影响 为了更好地确定小鼠的糖吞噬、胰岛素敏感性和能量代谢之间的联系， 申请人利用CRISPR/Cas 9技术构建了具有诱导性肝脏或骨骼的新型小鼠模型 GAA 的肌肉特异性敲除 该 K01 提案的首要目标是定义 GAA 的作用。 小鼠肝脏和骨骼肌的糖吞噬胰岛素敏感性和能量代谢。 申请人组建了一个跨学科赠款咨询小组，为 拟议的研究旨在建立申请人先前在新陈代谢方面的专业知识。 通过提供分析技术、研究概念、数据分析、资助和手稿方面的额外培训 写作、追踪方法的教学培训、建立富有成效的合作以及领导技能。 该提案将帮助申请人在糖吞噬领域启动自己的研究领域，并作为 他的独立研究生涯的跳板。