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
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAdipocytesAdipose tissueAttentionAutophagocytosisBindingBiochemicalBiochemistryBlood CirculationCellular biologyComplexCyclic AMP-Dependent Protein KinasesDataEndocrine GlandsEndoplasmic ReticulumGenesGeneticGoalsHigh Fat DietHomeostasisHormonalHormonesHumanHyperactivityImageInsulin ResistanceKnock-in MouseKnockout MiceLinkLoxP-flanked alleleLysosomesMaintenanceMediatingMetabolicMetabolic dysfunctionMetabolic syndromeMetabolismMolecularMusMutant Strains MiceMutationNon-Insulin-Dependent Diabetes MellitusPathway interactionsPharmacologyPhenocopyPhenotypePhosphotransferasesPlayProcessProteinsProteomicsReceptor SignalingRegulationResearchRoleSerumSignal TransductionSystemTestingTissuesVesicleadipokinesadiponectinfeedingglucose toleranceimprovedinsulin sensitivityinsulin sensitizing drugsmouse modelnovelpreventresponsetool
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Congcong He其他文献
Congcong He的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Congcong He', 18)}}的其他基金
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:
相似海外基金
Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
- 批准号:
2867610 - 财政年份:2023
- 资助金额:
$ 40万 - 项目类别:
Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
- 批准号:
BB/W009633/1 - 财政年份:2022
- 资助金额:
$ 40万 - 项目类别:
Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2021
- 资助金额:
$ 40万 - 项目类别:
Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
- 批准号:
459043 - 财政年份:2021
- 资助金额:
$ 40万 - 项目类别:
Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2020
- 资助金额:
$ 40万 - 项目类别:
Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10561642 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
- 批准号:
2243045 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10359032 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
- 批准号:
428988 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
Studentship Programs