Autophagy-facilitated secretion in metabolic maintenance

自噬促进代谢维持中的分泌

基本信息

  • 批准号:
    10490364
  • 负责人:
  • 金额:
    $ 40万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-17 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract The goal of this proposal is to demonstrate a novel non-degradative, non-cell autonomous, mechanism by which the autophagy machinery regulates metabolism. Although emerging evidence suggests that autophagy abnormality is implicated in metabolic dysfunction, the mechanism by which autophagy regulates insulin sensitivity is largely unknown. Autophagy is generally considered as a destruction and degradation process via lysosomes. We recently discovered a new non-degradative function regulated by a ULK1-Vps34-Becn1 autophagy machinery in adipose tissue, which may play a pivotal role in systemic AMPK activation and insulin sensitization. Adiponectin is an adipose-derived hormone (adipokine), whose reduction in circulation is strongly associated with type 2 diabetes (T2D) and metabolic syndrome. Hypoadiponectinemia caused by SNPs or mutations in the Adiponectin gene in humans has been associated with insulin resistance and T2D, and adiponectin knockout mice phenocopy the human phenotypes and develop insulin resistance. However, despite the functional importance of adiponectin, the mechanism that regulates adiponectin secretion has received little research attention and remains obscure. We found that autophagy-hyperactive mutant mice harboring an active mutation in the essential autophagy protein Becn1 (Becn1F121A knock-in mice) have improved insulin sensitivity in response to high-fat diet feeding, which is caused by factors in the circulation. To identify the Becn1-regulated, insulin-sensitizing, circulating factors, we performed a hormonal screen and identified a higher level of adiponectin in the serum of autophagy-hyperactive Becn1F121A mice. We found that on one hand, adipose- specific Becn1F121A expression is sufficient to improve systemic insulin sensitivity and increase circulating adiponectin levels; on the other hand, depleting Becn1, or inhibiting two upstream autophagy kinases, ULK1 and Vps34, reduces circulating adiponectin in mice. Using proteomic and biochemical approaches, we discovered that the exocyst component Sec6/Exoc3 is a binding partner of Becn1, and preferentially binds to the hyperactive form, Becn1F121A. Motivated by the preliminary data, we propose our overall hypothesis that a ULK1-Vps34- Becn1 autophagy axis improves insulin sensitivity by promoting adiponectin secretion via Becn1-exocyst binding in adipocytes. We term this pathway as “autophagy-facilitated secretion”. To test the hypothesis, we propose the following aims, using a combination of genetic, imaging, cell biology, biochemistry, and metabolic approaches: Aim 1 is to determine whether active Becn1 activates AMPK and improves insulin sensitivity via adiponectin signaling; Aim 2 is to determine whether a ULK1-Vps34-Becn1 autophagy axis functions in adipose tissue to non-cell autonomously regulate systemic insulin sensitivity; and Aim 3 is to demonstrate the molecular mechanism by which the Becn1-centered autophagy machinery regulates adiponectin secretion via the crosstalk with the exocyst pathway. Overall, our study will establish a new mechanistic paradigm for the Becn1-centered autophagy pathway in adipose tissue to prevent T2D, beyond its role in self-degradation.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Congcong He其他文献

Congcong He的其他文献

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{{ truncateString('Congcong He', 18)}}的其他基金

Autophagic regulation of cocaine abuse
可卡因滥用的自噬调节
  • 批准号:
    10838802
  • 财政年份:
    2022
  • 资助金额:
    $ 40万
  • 项目类别:
Autophagic regulation of cocaine abuse
可卡因滥用的自噬调节
  • 批准号:
    10503559
  • 财政年份:
    2022
  • 资助金额:
    $ 40万
  • 项目类别:
Autophagic regulation of cocaine abuse
可卡因滥用的自噬调节
  • 批准号:
    10682457
  • 财政年份:
    2022
  • 资助金额:
    $ 40万
  • 项目类别:
Autophagy-facilitated secretion in metabolic maintenance
自噬促进代谢维持中的分泌
  • 批准号:
    10367132
  • 财政年份:
    2021
  • 资助金额:
    $ 40万
  • 项目类别:
Autophagy-facilitated secretion in metabolic maintenance
自噬促进代谢维持中的分泌
  • 批准号:
    10665778
  • 财政年份:
    2021
  • 资助金额:
    $ 40万
  • 项目类别:
Mechanism of autophagy activation in exercise-induced anti-diabetic benefits
自噬激活在运动引起的抗糖尿病益处中的机制
  • 批准号:
    10522769
  • 财政年份:
    2017
  • 资助金额:
    $ 40万
  • 项目类别:
Mechanism of autophagy activation in exercise-induced anti-diabetic benefits
自噬激活在运动引起的抗糖尿病益处中的机制
  • 批准号:
    10704114
  • 财政年份:
    2017
  • 资助金额:
    $ 40万
  • 项目类别:
A novel autophagy gene beclin 2 in the prevention of type 2 diabetes and obesity
新型自噬基因 beclin 2 预防 2 型糖尿病和肥胖
  • 批准号:
    8774357
  • 财政年份:
    2014
  • 资助金额:
    $ 40万
  • 项目类别:
A novel autophagy gene beclin 2 in the prevention of type 2 diabetes and obesity
新型自噬基因 beclin 2 预防 2 型糖尿病和肥胖
  • 批准号:
    8989093
  • 财政年份:
    2014
  • 资助金额:
    $ 40万
  • 项目类别:
A novel autophagy gene beclin 2 in the prevention of type 2 diabetes and obesity
新型自噬基因 beclin 2 预防 2 型糖尿病和肥胖
  • 批准号:
    8538967
  • 财政年份:
    2012
  • 资助金额:
    $ 40万
  • 项目类别:

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