METABOLIC IMPACTS OF TYPE II INTERFERON SIGNALS IN OBESITY
II 型干扰素信号对肥胖的代谢影响
基本信息
- 批准号:10775353
- 负责人:
- 金额:$ 19.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdipocytesAdipose tissueAdverse effectsAwardChronicDiabetic mouseEducational process of instructingGenetic TranscriptionGoalsGrantHigh Fat DietHumanIFNGR1 geneImmune systemInflammationInflammatoryInsulin ResistanceInterferon Type IIKnowledgeMediatingMetabolicMetabolismMitochondriaNon-Insulin-Dependent Diabetes MellitusObesityOutcomeOvernutritionPathogenicityPathway interactionsPhenotypeRepressionSTAT1 geneSignal TransductionTissue ExpansionTranscriptional ActivationTranscriptional RegulationWeight Gaincomorbidityenergy balanceinsulin sensitivitynovelprogramsresponsetranscription factortransmission process
项目摘要
ABSTRACT
Obesity coincides with pro-inflammatory phenotypes in adipose tissues and the insulin resistance that precedes
type 2 diabetes. Despite a wealth of evidence, causal relationships between obesity-induced inflammation and
insulin resistance remain unknown. In the last grant cycle, we explored how inflammation uncouples obesity
from insulin resistance. We showed blocking interferon gamma (IFNg) activation of the transcription factor STAT1
limits pro-inflammatory programs that would otherwise restrict white adipose tissue (WAT) expansion and
decrease insulin sensitivity. We also demonstrated complete elimination of IFNg activity mediates many adverse
effects of high fat diet, including weight gain, diminished mitochondrial function, and insulin resistance. Multiple
studies, including our own, observed higher STAT1 expression in WAT of diabetic mice and humans, suggesting
that IFNg activity may still represent a pathogenic consequence of chronic obesity. The goal of the current cycle
is to fill vital remaining gaps in our mechanistic understanding of the fundamental ways IFNg transmits signals to
transcriptional regulation of metabolism and insulin sensitivity in fat cells. To achieve our goal, we will
demonstrate that the IFNg receptor in WAT initiates the metabolic decrement of overnutrition (Aim 1) and
establish the downstream transcriptional outcomes of IFNg that repress cellular energy balance in the fat cell
(Aim 2). Lastly, we will determine whether obesity-associated inflammation restricts a novel pathway that
supports lipogenic responses necessary to sustain WAT expansion (Aim 3). Ultimately, such knowledge will
teach us how to leverage the immune system to treat obesity and its co-morbidities.
摘要
肥胖与脂肪组织中的促炎表型和之前的胰岛素抵抗相一致
2型糖尿病尽管有大量的证据,肥胖引起的炎症和肥胖之间的因果关系仍然存在。
胰岛素抵抗仍然未知。在上一个资助周期中,我们探讨了炎症如何使肥胖脱钩
胰岛素抵抗我们发现阻断干扰素γ(IFNg)激活转录因子STAT1,
限制促炎程序,否则会限制白色脂肪组织(WAT)扩张,
降低胰岛素敏感性。我们还证明了IFNg活性的完全消除介导了许多不良反应。
高脂肪饮食的影响,包括体重增加、线粒体功能减弱和胰岛素抵抗。多
包括我们自己的研究在内的研究观察到,糖尿病小鼠和人类的WAT中STAT1表达较高,这表明
IFNg活性可能仍然代表慢性肥胖的致病结果。本周期的目标
是填补我们对IFNg传输信号的基本方式的机械理解中的重要空白,
脂肪细胞中的代谢和胰岛素敏感性的转录调节。为了实现我们的目标,我们将
证明WAT中的IFNg受体启动营养过剩的代谢减少(目标1),
建立抑制脂肪细胞中细胞能量平衡的IFNg的下游转录结果
(Aim 2)的情况。最后,我们将确定肥胖相关的炎症是否限制了一种新的途径,
支持维持WAT扩增所必需的脂肪生成反应(Aim 3)。最终,这些知识将
教我们如何利用免疫系统来治疗肥胖及其并发症。
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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Sean Hartig其他文献
Sean Hartig的其他文献
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{{ truncateString('Sean Hartig', 18)}}的其他基金
An anti-diabetic microRNA that promotes metabolically healthy obesity
一种抗糖尿病 microRNA,可促进代谢健康的肥胖
- 批准号:
9367450 - 财政年份:2017
- 资助金额:
$ 19.77万 - 项目类别:
Metabolic Impacts of Type II Interferon Signals in Obesity
II 型干扰素信号对肥胖的代谢影响
- 批准号:
10665744 - 财政年份:2017
- 资助金额:
$ 19.77万 - 项目类别:
An anti-diabetic microRNA that promotes metabolically healthy obesity
一种抗糖尿病的 microRNA,可促进代谢健康的肥胖
- 批准号:
10163161 - 财政年份:2017
- 资助金额:
$ 19.77万 - 项目类别:
Metabolic Impacts of Type II Interferon Signals in Obesity
II 型干扰素信号对肥胖的代谢影响
- 批准号:
10900013 - 财政年份:2017
- 资助金额:
$ 19.77万 - 项目类别:
Regulation of SYSTEMIC INSULIN SENSITIVITY by miRNA-30a
miRNA-30a 对全身胰岛素敏感性的调节
- 批准号:
9111200 - 财政年份:2016
- 资助金额:
$ 19.77万 - 项目类别:
Regulation of SYSTEMIC INSULIN SENSITIVITY by miRNA-30a
miRNA-30a 对全身胰岛素敏感性的调节
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9217647 - 财政年份:2016
- 资助金额:
$ 19.77万 - 项目类别:
Unique Roles of p160 Coactivators during Human Adipogenesis
p160 共激活剂在人类脂肪形成过程中的独特作用
- 批准号:
7804266 - 财政年份:2009
- 资助金额:
$ 19.77万 - 项目类别:
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