ADK Regulation of Fat Metabolism and Insulin Sensitivity

ADK 对脂肪代谢和胰岛素敏感性的调节

基本信息

批准号：
10373007
负责人：
Chaodong Wu
金额：
$ 45.53万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373007
关键词：
Adenosine Adenosine Kinase Adenosine Monophosphate Anti-Inflammatory Agents Body fat Chronic Disease DNA Methylation Deposition Development Diet Disease Ensure Enzymes Fatty Liver Fatty acid glycerol esters Fibrinogen Genes Hepatic Hepatocyte High Fat Diet Homeostasis Impairment In Vitro Inflammation Inflammatory Inflammatory Response Insulin Resistance Knowledge Kupffer Cells Link Lipids Liver Macrophage Activation Metabolic Metabolic Diseases Methionine Methylation Mitochondrial DNA Mus Myeloid Cells Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Organ Prevention Process Reaction Receptor Signaling Regulation Research Role Severities Testing base experimental study extracellular fatty acid oxidation in vivo insulin sensitivity insulin signaling ketogenesis lipid metabolism liver inflammation macrophage novel obesity management obesity treatment overexpression prevent receptor response response to injury

项目摘要

Excessive deposition of fats in hepatocytes causes inflammation and impairs insulin signaling, which in turn promotes the development of systemic insulin resistance and metabolic dysregulation. As the enzyme that phosphorylates adenosine, adenosine kinase (ADK) is expressed at the highest levels in the liver and critically determines the levels of both intracellular and extracellular adenosine. However, precisely how ADK regulates hepatic and systemic fat metabolism in relation to whole body insulin sensitivity is unknown. For this project, the ADK in hepatocytes has been validated to promote hepatic fat deposition and increase whole body fat mass in mice. Additional preliminary results also indicate: 1) hepatocyte-specific ADK overexpression in mice increases liver inflammation and causes systemic insulin resistance whereas hepatocyte-specific ADK disruption in mice decreases the severity of high-fat diet (HFD)-induced insulin resistance; 2) ADK disruption increases hepatic and macrophage expression of adenosine 2A receptor (A2AR), whose disruption increases hepatic ADK amount, exacerbates diet-induced hepatic fat accumulation and insulin resistance, impairs hepatocyte insulin signaling, and stimulates macrophage proinflammatory (M1) activation; and 3) DNA methylation was decreased in livers of hepatocyte-specific ADK-deficient mice and in macrophages from myeloid cell-specific ADK-deficient mice. Based on these findings, this project will test the central hypothesis that excessive ADK acts through dysregulating hepatocyte-macrophage crosstalk to promote hepatic fat deposition, impair liver insulin signaling, and increase liver inflammation, thereby bringing about hepatic and systemic insulin resistance. Mechanistically, ADK actions involve impaired A2AR signaling and increased DNA methylation within genes for hepatocyte fatty acid oxidation and macrophage anti-inflammatory responses. Accordingly, three Specific Aims will be pursued. Aim 1: Define the role of hepatocyte ADK in regulating fat metabolism and insulin sensitivity. In vivo experiments will be performed to examine the extent to which hepatocyte-specific ADK overexpression or disruption alters the severity of HFD-induced hepatic fat deposition, inflammation, and insulin resistance. In vitro experiments will be used to examine how ADK-driven hepatocyte factors alter the inflammatory status of macrophages/Kupffer cells. Aim 2: Define the role of macrophage ADK in regulating fat metabolism and insulin sensitivity. In vivo xperiments will be performed to examine the extent to which myeloid cell-specific ADK overexpression or disruption alters the severity of HFD-induced hepatic fat deposition, inflammation, and insulin resistance. In vitro experiments will be performed to examine whether and how ADK-driven macrophage factors promote hepatocyte fat deposition and inflammatory responses. Aim 3: Determine the extent to which ADK acts through decreasing A2AR signaling and/or increasing DNA methylation to impair hepatocyte fat metabolism and insulin signaling and enhance macrophage M1 activation. The successful completion of this project will accelerate the development of novel ADK inhibition-based approaches for managing obesity-associated chronic diseases.

肝细胞中脂肪过度沉积会引起炎症并损害胰岛素信号传导，进而促进全身胰岛素抵抗和代谢失调的发展。作为磷酸化腺苷的酶，腺苷激酶 (ADK) 在肝脏中表达水平最高，并关键地决定细胞内和细胞外腺苷的水平。然而，ADK 究竟如何调节与全身胰岛素敏感性相关的肝脏和全身脂肪代谢尚不清楚。在该项目中，肝细胞中的 ADK 已被验证可促进小鼠肝脏脂肪沉积并增加全身脂肪量。其他初步结果还表明：1) 小鼠中肝细胞特异性 ADK 过度表达会增加肝脏炎症并导致全身胰岛素抵抗，而小鼠中肝细胞特异性 ADK 破坏会降低高脂饮食 (HFD) 诱导的胰岛素抵抗的严重程度； 2）ADK破坏增加肝脏和巨噬细胞腺苷2A受体（A2AR）的表达，腺苷2A受体（A2AR）的破坏增加肝脏ADK的量，加剧饮食诱导的肝脏脂肪积累和胰岛素抵抗，损害肝细胞胰岛素信号传导，并刺激巨噬细胞促炎细胞（M1）激活； 3) 肝细胞特异性 ADK 缺陷小鼠的肝脏和骨髓细胞特异性 ADK 缺陷小鼠的巨噬细胞中 DNA 甲基化降低。基于这些发现，该项目将检验一个中心假设，即过量的ADK通过调节肝细胞-巨噬细胞串扰来促进肝脏脂肪沉积，损害肝脏胰岛素信号传导，并增加肝脏炎症，从而导致肝脏和全身胰岛素抵抗。从机制上讲，ADK 的作用涉及 A2AR 信号传导受损以及肝细胞脂肪酸氧化和巨噬细胞抗炎反应基因内 DNA 甲基化增加。因此，将追求三个具体目标。目标 1：明确肝细胞 ADK 在调节脂肪代谢和胰岛素敏感性中的作用。将进行体内实验，以检查肝细胞特异性 ADK 过度表达或破坏在多大程度上改变 HFD 诱导的肝脏脂肪沉积、炎症和胰岛素抵抗的严重程度。体外实验将用于检查 ADK 驱动的肝细胞因子如何改变巨噬细胞/库普弗细胞的炎症状态。目标 2：明确巨噬细胞 ADK 在调节脂肪代谢和胰岛素敏感性中的作用。将进行体内实验来检查骨髓细胞特异性 ADK 过度表达或破坏在多大程度上改变 HFD 诱导的肝脏脂肪沉积、炎症和胰岛素抵抗的严重程度。将进行体外实验来检查 ADK 驱动的巨噬细胞因子是否以及如何促进肝细胞脂肪沉积和炎症反应。目标 3：确定 ADK 在多大程度上通过减少 A2AR 信号传导和/或增加 DNA 甲基化来损害肝细胞脂肪代谢和胰岛素信号传导并增强巨噬细胞 M1 活化。该项目的成功完成将加速开发基于 ADK 抑制的新型方法，用于治疗与肥胖相关的慢性疾病。