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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：
10597081
负责人：
Chaodong Wu
金额：
$ 43.91万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597081
关键词：
Acceleration 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 Genes Hepatic Hepatocyte High Fat Diet Homeostasis Impairment In Vitro Inflammation Inflammatory Inflammatory Response Insulin Resistance Knowledge Kupffer Cells Link Lipids Liver Macrophage Macrophage Activation Metabolic Metabolic Diseases Methionine Methylation Mitochondrial DNA Mus Myeloid Cells Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Organ Phosphorylation Prevention Process Reaction Receptor Signaling Regulation Research Role Severities Testing experimental study extracellular fatty acid oxidation in vivo insulin sensitivity insulin signaling ketogenesis lipid metabolism liver inflammation novel obesity management obesity treatment overexpression prevent receptor 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.

脂肪在肝细胞中的过度沉积引起炎症并损害胰岛素信号传导，这反过来又促进全身性胰岛素抵抗和代谢失调的发展。作为腺苷磷酸化的酶，腺苷激酶（ADK）在肝脏中以最高水平表达，并决定细胞内和细胞外腺苷的水平。然而，ADK究竟如何调节肝脏和全身脂肪代谢与全身胰岛素敏感性的关系尚不清楚。对于该项目，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。另外的初步结果还表明：1）小鼠中肝细胞特异性ADK过表达增加肝脏炎症并引起全身性胰岛素抵抗，而小鼠中肝细胞特异性ADK破坏降低高脂饮食（HFD）诱导的胰岛素抵抗的严重程度; 2）ADK破坏增加腺苷2A受体（A2 AR）的肝和巨噬细胞表达，其破坏增加肝ADK量，加剧饮食诱导的肝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（M1）活化;和3）在肝细胞特异性ADK缺陷小鼠的肝脏和来自骨髓细胞特异性ADK缺陷小鼠的巨噬细胞中，DNA甲基化降低。基于这些发现，该项目将测试中心假设，即过量ADK通过失调肝细胞-巨噬细胞串扰促进肝脏脂肪沉积，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A2 AR信号传导受损和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。目的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过表达或破坏改变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/枯否细胞的炎症状态。目的2：探讨巨噬细胞ADK在调节脂肪代谢和胰岛素敏感性中的作用。将进行体内实验以检查髓样细胞特异性ADK过表达或破坏改变HFD诱导的肝脂肪沉积、炎症和胰岛素抵抗的严重程度。将进行体外实验以检查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。目标三：确定ADK通过降低A2 AR信号和/或增加DNA甲基化来损害肝细胞脂肪代谢和胰岛素信号并增强巨噬细胞M1活化的程度。该项目的成功完成将加速开发基于ADK抑制的新方法，用于管理肥胖相关慢性疾病。