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表型以及先于胰岛素抵抗的现象相一致 2型糖尿病。尽管有大量证据，但肥胖引起的炎症与肥胖之间的因果关系 胰岛素抵抗仍然未知。在上一个资助周期中，我们探索了炎症如何消除肥胖 来自胰岛素抵抗。我们展示了阻断转录因子 STAT1 的干扰素 γ (IFNg) 激活 限制促炎程序，否则会限制白色脂肪组织（WAT）的扩张和 降低胰岛素敏感性。我们还证明完全消除 IFNg 活性会介导许多不良反应 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。多种的 包括我们自己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后果。本周期的目标 的目的是填补我们对 IFNg 向细胞传递信号的基本方式的机械理解中尚存的重要空白。 脂肪细胞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） 建立抑制脂肪细胞能量平衡的 IFNg 下游转录结果 （目标 2）。最后，我们将确定肥胖相关炎症是否限制了一种新的途径 支持维持 WAT 扩张所需的脂肪生成反应（目标 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。