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.

摘要 肥胖与脂肪组织中的促炎表型和先于胰岛素抵抗的症状相吻合 2型糖尿病。尽管有大量证据表明，肥胖引起的炎症和肥胖之间的因果关系 胰岛素抵抗仍不清楚。在上一个拨款周期中，我们探索了炎症是如何导致肥胖的。 由胰岛素抵抗引起。我们发现阻断了转录因子STAT1的干扰素-γ(IFNG)激活 限制促炎计划，否则将限制白色脂肪组织(WAT)的扩张和 降低胰岛素敏感性。我们还证明了完全消除IFNG活性会介导许多不利的 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。多重 包括我们自己的研究，观察到糖尿病小鼠和人类WAT中更高的STAT1表达，这表明 IFNG活性可能仍代表慢性肥胖症的致病后果。当前周期的目标是 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剩余空白 脂肪细胞代谢和胰岛素敏感性的转录调控。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)和 建立抑制脂肪细胞中细胞能量平衡的IFNG下游转录结果 (目标2)。最后，我们将确定肥胖相关的炎症是否限制了一种新的途径，即 支持维持WAT扩张所必需的造脂反应(目标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症及其共病。