Endoplasmic Reticulum Chaperone as a Regulator of Obesity and Diabetes

内质网伴侣作为肥胖和糖尿病的调节剂

基本信息

  • 批准号:
    7729682
  • 负责人:
  • 金额:
    $ 39.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-20 至 2011-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The endoplasmic reticulum (ER) is a cellular organelle where secretory and membrane-associated proteins are synthesized and modified. It has been proposed that obesity promotes nutrient stress and chronic inflammation that involve increased demand on the synthetic machinery of the cells in many secretory organ systems, such as adipose tissue. Thus, obesity acts as a chronic stimulus for ER stress in peripheral tissues, triggering insulin resistance and type 2 diabetes. The multifunctional ER chaperone protein GRP78/BiP, is a master regulator of ER homeostasis due to its control of protein folding and the activation of trans-membrane ER stress sensors. Serendipitously, we discovered that the Grp78 mice in the C57BL/6 background exhibit resistance to high-fat diet (HFD)-induced obesity and improved insulin sensitivity. Our preliminary studies revealed that HFD-fed Grp78 mice showed increased energy expenditure without changes in food intake and lipid absorption. Preliminary euglycemic clamp studies showed a striking increase in insulin-stimulated glucose uptake most prominently in the white adipose tissue of the Grp78 mice (P<0.001). We further discovered that in adipose tissue, Grp78 heterozygosity leads to diet-induced upregulation of ER chaperones. In contrast, glucose metabolism was not altered in skeletal muscle and no chaperone upregulation was observed. Thus, Grp78 mice offer new opportunities to investigate the basic mechanisms linking ER integrity to energy balance, glucose homeostasis and adipocyte stress. We propose that during chronic stress induced by HFD, Grp78 heterozygosity in adipose tissue triggers compensatory and protective measures, such as upregulation of chaperones and increase in mitochondrial function, which lead to enhanced energy expenditure, attenuation of ER stress and inflammatory responses resulting in improved insulin sensitivity. Based on our preliminary data that the Grp78mice are more insulin sensitive than the wild-type littermates on chow diet with similar body weights, Aim 1 will identify the mechanism by which Grp78 improves insulin sensitivity. Aim 2 will determine how obesity affects the unfolded protein response signaling and how Grp78 heterozygosity alters energy expenditure and causes resistance to diet-induced obesity. Aim 3 will generate and characterize mouse models with white adipose tissue-specific overexpression or knockout of GRP78 to determine its role in energy balance and insulin sensitivity. Aim 4 will determine the functional contribution of other ER chaperones upregulated in adipose tissue of HFD-fed Grp78 mice in adipocyte metabolic function, utilizing primary adipocytes and MEFs from the Grp78 and mice, as well as the 3T3-L1 adipocyte culture system. The clinical relevance of our studies is that they may identify novel regulatory pathways for diet- induced obesity and insulin resistance which may represent new therapeutic targets for human metabolic diseases. PUBLIC HEALTH RELEVANCE: The dramatic increase in the incidence of obesity, insulin resistance and type 2 diabetes has become one of the most serious threats to human health. Hence, understanding the molecular mechanisms underlying these diseases is critical. This proposal is based on the serendipitous observation from a novel mouse model recently created in the laboratory that may provide clues to prevent high-fat diet-induced obesity and subsequent insulin resistance. This proposal will fully characterize the metabolic phenotypes of the mutant mice and investigate the underlying mechanisms for increased energy expenditure and improved insulin sensitivity of these mice under the chronic stress of high-fat diet. If validated, our findings may lead to new targets for therapy against obesity and type 2 diabetes in humans.
描述(由申请人提供):内质网(ER)是一种细胞器,分泌蛋白和膜相关蛋白在其中合成和修饰。有人提出,肥胖会促进营养应激和慢性炎症,从而增加对许多分泌器官系统(例如脂肪组织)细胞合成机制的需求。因此,肥胖会长期刺激外周组织内质网应激,引发胰岛素抵抗和 2 型糖尿病。多功能内质网伴侣蛋白 GRP78/BiP 由于其控制蛋白质折叠和跨膜内质网应激传感器的激活而成为内质网稳态的主要调节因子。偶然地,我们发现 C57BL/6 背景下的 Grp78 小鼠表现出对高脂饮食 (HFD) 诱导的肥胖的抵抗力并改善了胰岛素敏感性。我们的初步研究表明,高脂饮食喂养的 Grp78 小鼠表现出能量消耗增加,但食物摄入和脂质吸收没有变化。初步的正常血糖钳夹研究显示,Grp78 小鼠的白色脂肪组织中胰岛素刺激的葡萄糖摄取显着增加(P<0.001)。我们进一步发现,在脂肪组织中,Grp78 杂合性导致饮食诱导的 ER 伴侣上调。相反,骨骼肌中的葡萄糖代谢没有改变,也没有观察到伴侣的上调。因此,Grp78 小鼠提供了新的机会来研究将 ER 完整性与能量平衡、葡萄糖稳态和脂肪细胞应激联系起来的基本机制。我们提出,在 HFD 引起的慢性应激期间,脂肪组织中的 Grp78 杂合性会触发补偿和保护措施,例如伴侣的上调和线粒体功能的增加,从而导致能量消耗增加、内质网应激和炎症反应减弱,从而改善胰岛素敏感性。根据我们的初步数据,即 Grp78 小鼠比体重相似的饮食的野生型同窝小鼠对胰岛素更敏感,目标 1 将确定 Grp78 改善胰岛素敏感性的机制。目标 2 将确定肥胖如何影响未折叠蛋白反应信号传导,以及 Grp78 杂合性如何改变能量消耗并导致对饮食引起的肥胖的抵抗。目标 3 将生成并表征白色脂肪组织特异性过度表达或敲除 GRP78 的小鼠模型,以确定其在能量平衡和胰岛素敏感性中的作用。目标 4 将利用来自 Grp78 和小鼠的原代脂肪细胞和 MEF,以及 3T3-L1 脂肪细胞培养系统,确定 HFD 喂养的 Grp78 小鼠脂肪组织中上调的其他 ER 伴侣对脂肪细胞代谢功能的功能贡献。我们研究的临床意义在于,它们可能会发现饮食引起的肥胖和胰岛素抵抗的新调节途径,这可能代表人类代谢疾病的新治疗靶点。公共卫生相关性:肥胖、胰岛素抵抗和 2 型糖尿病的发病率急剧增加,已成为对人类健康最严重的威胁之一。因此,了解这些疾病的分子机制至关重要。该提议基于实验室最近创建的新型小鼠模型的偶然观察,该模型可能为预防高脂肪饮食引起的肥胖和随后的胰岛素抵抗提供线索。该提案将全面表征突变小鼠的代谢表型,并研究这些小鼠在高脂肪饮食的慢性应激下增加能量消耗和改善胰岛素敏感性的潜在机制。如果得到验证,我们的研究结果可能会带来治疗人类肥胖和 2 型糖尿病的新目标。

项目成果

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AMY S LEE其他文献

AMY S LEE的其他文献

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{{ truncateString('AMY S LEE', 18)}}的其他基金

Targeting Cancer through Suppressing Stress Induction of GRP78/BiP
通过抑制 GRP78/BiP 的应激诱导来靶向癌症
  • 批准号:
    10310435
  • 财政年份:
    2019
  • 资助金额:
    $ 39.71万
  • 项目类别:
Targeting Cancer through Suppressing Stress Induction of GRP78/BiP
通过抑制 GRP78/BiP 的应激诱导来靶向癌症
  • 批准号:
    9883506
  • 财政年份:
    2019
  • 资助金额:
    $ 39.71万
  • 项目类别:
Targeting Cancer through Suppressing Stress Induction of GRP78/BiP
通过抑制 GRP78/BiP 的应激诱导来靶向癌症
  • 批准号:
    10063863
  • 财政年份:
    2019
  • 资助金额:
    $ 39.71万
  • 项目类别:
Targeting Cell Surface GRP78 as a Novel Therapy for Pancreatic Cancer
靶向细胞表面 GRP78 作为胰腺癌的新疗法
  • 批准号:
    8836986
  • 财政年份:
    2014
  • 资助金额:
    $ 39.71万
  • 项目类别:
Targeting Cell Surface GRP78 as a Novel Therapy for Pancreatic Cancer
靶向细胞表面 GRP78 作为胰腺癌的新疗法
  • 批准号:
    8700022
  • 财政年份:
    2014
  • 资助金额:
    $ 39.71万
  • 项目类别:
Endoplasmic Reticulum Chaperone as a Regulator of Obesity and Diabetes
内质网伴侣作为肥胖和糖尿病的调节剂
  • 批准号:
    7896679
  • 财政年份:
    2009
  • 资助金额:
    $ 39.71万
  • 项目类别:
STRESS INDUCTION OF GLUCOSE REGULATED PROTEIN GRP78/BiP
葡萄糖调节蛋白 GRP78/BiP 的应激诱导
  • 批准号:
    7848451
  • 财政年份:
    2009
  • 资助金额:
    $ 39.71万
  • 项目类别:
MECHANISM OF ANTI-APOPTOTIC FUNCTION OF GRP78/BiP
GRP78/BiP的抗凋亡作用机制
  • 批准号:
    6966322
  • 财政年份:
    2005
  • 资助金额:
    $ 39.71万
  • 项目类别:
A NOVEL TRANSGENIC MOUSE MODEL FOR DIABETES
一种新型糖尿病转基因小鼠模型
  • 批准号:
    6898106
  • 财政年份:
    2005
  • 资助金额:
    $ 39.71万
  • 项目类别:
A NOVEL TRANSGENIC MOUSE MODEL FOR DIABETES
一种新型糖尿病转基因小鼠模型
  • 批准号:
    7052768
  • 财政年份:
    2005
  • 资助金额:
    $ 39.71万
  • 项目类别:

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