Integration of innate immune function and metabolism by the TBK1-mTOR axis

TBK1-mTOR 轴整合先天免疫功能和代谢

基本信息

批准号：
10161014
负责人：
Diane C. Fingar
金额：
$ 15.6万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2020-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161014
关键词：
Adipocytes Adipose tissue Agonist Alleles Anti-Inflammatory Agents Body Weight Catalytic Domain Cell physiology Cellular Metabolic Process Complex Cues Deposition Diabetes Mellitus Diet Disease Exhibits FRAP1 gene Gene Targeting Glucose Growth Factor Hepatocyte Homeostasis Host Defense Hyperglycemia Hyperinsulinism IL10 gene Immune Immune System Diseases Impairment Inflammation Inflammatory Inflammatory Response Insulin Insulin Resistance Interferon Type I Interferon-beta Interferons Interleukin-10 Knock-in Knock-in Mouse Knock-out Knockout Mice Link Lipids Lipolysis Liver Mediating Metabolic Metabolic Control Metabolic Diseases Metabolism Microbe Modeling Multiprotein Complexes Mus Muscle Myelogenous Non-Insulin-Dependent Diabetes Mellitus Nutrient Obese Mice Obesity Pathogenesis Phenotype Phosphorylation Phosphotransferases Physiological Physiology Prevalence Production Raptors Regulation Reporting Resistance Role Signal Transduction Site System TBK1 gene Testing Therapeutic Triglycerides Work base blood glucose regulation cell growth cytokine differential expression glucose production glucose tolerance glucose uptake glycemic control hepatic gluconeogenesis immune function in vivo innate immune function insulin sensitivity lipid biosynthesis macrophage mouse model novel therapeutics response sensor transcriptome sequencing

项目摘要

Project Summary Obesity-linked diabetes represents a complex metabolic disorder with increasing prevalence worldwide. The conserved kinase mTOR (mechanistic target of rapamycin), which comprises the catalytic core of two functionally distinct multiprotein complexes (raptor-containing mTORC1 and rictor-containing mTORC2), promotes glucose and lipid homeostasis in vivo. mTOR functions as a conserved nutrient sensor that integrates a diverse array of local and systemic signals to control cell metabolism and cell growth. Aberrant mTOR function contributes to type II diabetes and a variety of immune disorders (among other diseases). Despite the physiologic importance of mTOR, major gaps exist in our basic understanding of mTOR regulation and function and how mTOR cooperates with other signaling systems to control integrative physiology. Recent work from our lab (Bodur et al. EMBO J 2018) provides the scientific premise for this proposal, demonstrating that the innate immune kinase TBK1 phosphorylates mTOR (on S2159) directly to activate mTORC1 and mTORC2 signaling. Moreover, the ability of TBK1 to promote production of IFNb, a type I interferon that initiates first-line host defense against infectious microbes, requires mTOR S2159 phosphorylation and mTORC1 activity. This work directly linked two signaling systems not previously known to functionally interact. As prior work reported that adipocyte- specific Tbk1 knockout (KO) causes systemic insulin resistance in mice (as does adipocyte-specific KO of Mtor, Raptor (mTORC1), or Rictor (mTORC2)), we decided to investigate a potential role for TBK1-mTOR signaling in metabolic control by generating a “TBK1 resistant” mTOR knock-in mouse allele bearing non-phosphorylatable Ala at S2159 (MtorA). Our preliminary results indicate that diet-induced obese (DIO) MtorA/A mice exhibit insulin resistance, hyperinsulinemia, and hyperglycemia despite unchanged body weight and adiposity relative to DIO controls. Our central hypothesis posits that TBK1-mTOR signaling protects against insulin resistance and hyperglycemia during obesity. Specifically, we hypothesize that that TBK1-mTOR signaling in adipose tissue promotes nutrient storage in adipocytes and protects from ectopic lipid deposition and insulin resistance during obesity. We thus further postulate that TBK1-mTORC1 signaling in adipocytes and macrophages mediates anti- inflammatory responses that promote systemic insulin sensitivity and glycemic control during DIO. To define roles for adipocyte and macrophage-specific TBK1-mTOR signaling in metabolic control, we will determine the mechanisms by which adipocyte TBK1-mTOR signaling promotes glucose homeostasis during obesity (Aim 1) and define the role of TBK1-mTOR signaling in macrophages for control of innate immune function and glycemic control during obesity (Aim 2). In addition to defining physiologic roles for TBK1-mTOR signaling in vivo, this project will enhance our understanding of mechanisms that integrate innate immune and metabolic responses and protect against obesity-linked type II diabetes- revealing potential new therapeutic opportunities.

项目概要与肥胖相关的糖尿病是一种复杂的代谢性疾病，在全球范围内患病率不断增加。保守激酶 mTOR（雷帕霉素的机制靶点），包含两个催化核心功能不同的多蛋白复合物（含有 raptor 的 mTORC1 和含有 rictor 的 mTORC2）， mTOR 作为整合的保守营养传感器促进体内葡萄糖和脂质稳态。控制细胞代谢和细胞生长的多种局部和全身信号。尽管有生理学原因，但仍会导致 II 型糖尿病和各种免疫疾病（以及其他疾病）。 mTOR 的重要性，但我们对 mTOR 调节和功能以及如何实现的基本理解存在重大差距 mTOR 与其他信号系统合作控制综合生理学。（Bodur 等人 EMBO J 2018）为这一提议提供了科学前提，证明了先天性免疫激酶 TBK1 直接磷酸化 mTOR（位于 S2159）以激活 mTORC1 和 mTORC2 信号传导。此外，TBK1 能够促进 IFNb 的产生，IFNb 是一种启动一线宿主防御的 I 型干扰素对抗传染性微生物，需要 mTOR S2159 磷酸化和 mTORC1 活性直接发挥作用。正如先前的研究报道，脂肪细胞连接了两个以前未知的功能相互作用的信号系统。特异性 Tbk1 敲除 (KO) 会导致小鼠全身胰岛素抵抗（Mtor 的脂肪细胞特异性敲除也会导致系统性胰岛素抵抗）， Raptor (mTORC1) 或 Rictor (mTORC2))，我们决定研究 TBK1-mTOR 信号传导在通过生成带有不可磷酸化的“TBK1 抗性”mTOR 敲入小鼠等位基因来控制代谢我们的初步结果表明饮食诱导肥胖 (DIO) MtorA/A 小鼠表现出胰岛素。与 DIO 相比，尽管体重和肥胖程度不变，但仍存在抵抗力、高胰岛素血症和高血糖我们的中心假设认为 TBK1-mTOR 信号传导可防止胰岛素抵抗和具体来说，我们合作研究了脂肪组织中的 TBK1-mTOR 信号传导。促进脂肪细胞中的营养储存，并防止异位脂质沉积和胰岛素抵抗因此，我们进一步假设脂肪细胞和巨噬细胞中的 TBK1-mTORC1 信号介导抗肥胖。 DIO 期间促进全身胰岛素敏感性和血糖控制的炎症反应。为了了解脂肪细胞和巨噬细胞特异性 TBK1-mTOR 信号在代谢控制中的作用，我们将确定脂肪细胞 TBK1-mTOR 信号传导促进肥胖期间葡萄糖稳态的机制（目标 1）并定义 TBK1-mTOR 信号在巨噬细胞中控制先天免疫功能和血糖的作用肥胖期间的控制（目标 2）除了定义体内 TBK1-mTOR 信号传导的生理作用外，该项目将增强我们对整合先天免疫和代谢反应机制的理解并预防与肥胖相关的 II 型糖尿病——揭示了潜在的新治疗机会。