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: 10775353
• 负责人: Sean Hartig
• 金额: $ 19.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10775353
• 关键词: Adipocytes; Adipose tissue; Adverse effects; Award; Chronic; Diabetic mouse; Educational process of instructing; Genetic Transcription; Goals; Grant; High Fat Diet; Human; IFNGR1 gene; Immune system; Inflammation; Inflammatory; Insulin Resistance; Interferon Type II; Knowledge; Mediating; Metabolic; Metabolism; Mitochondria; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overnutrition; Pathogenicity; Pathway interactions; Phenotype; Repression; STAT1 gene; Signal Transduction; Tissue Expansion; Transcriptional Activation; Transcriptional Regulation; Weight Gain; comorbidity; energy balance; insulin sensitivity; novel; programs; response; transcription factor; transmission process

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.

抽象的 肥胖与脂肪组织中的促炎性表型和先前的胰岛素抵抗相吻合 2型糖尿病。尽管有大量证据，但肥胖引起的炎症与 胰岛素抵抗仍然未知。在上一个赠款周期中，我们探索了炎症如何肥胖 来自胰岛素抵抗。我们显示了转录因子STAT1的阻塞干扰素γ（IFNG）激活 限制促炎计划，否则将限制白色脂肪组织（WAT）的扩展和 降低胰岛素敏感性。我们还证明了对IFNG活动的完全消除介导了许多不利 高脂肪饮食的影响，包括体重增加，线粒体功能降低和胰岛素抵抗。多种的 研究，包括我们自己的研究，观察到糖尿病小鼠和人类的WAT中较高的STAT1表达，这表明 IFNG活性仍然可能代表慢性肥胖症的致病结果。当前周期的目标 是在我们对基本方式的机械理解中填补重要的剩余空白，即如果将信号传输到 脂肪细胞中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受体会启动营养不良的代谢减少（AIM 1）和 建立抑制脂肪细胞中细胞能量平衡的IFNG的下游转录结果 （目标2）。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 支持维持扩展所需的脂肪生成反应（AIM 3）。最终，这样的知识将 教我们如何利用免疫系统来治疗肥胖及其合并症。