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

• 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
• 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

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.

项目摘要 与肥胖相关的糖尿病代表了一种复杂的代谢障碍，全球患病率不断增加。 保守激酶MTOR（雷帕霉素的机械靶标），其中包括两个的催化核心 在功能上不同的多蛋白质复合物（含猛禽的MTORC1和含Rictor的MTORC2）， 在体内促进葡萄糖和脂质稳态。 MTOR充当整合的配置营养传感器 一系列局部和全身信号的潜水员来控制细胞代谢和细胞生长。异常MTOR功能 有助于II型糖尿病和各种免疫疾病（除其他疾病）。尽管有生理 MTOR的重要性，我们对MTOR调节和功能的基本理解以及如何 MTOR与其他信号系统合作以控制综合生理。我们实验室的最新工作 （Bodur等人Embo J 2018）为该提案提供了科学前提，证明了先天性 免疫激酶TBK1磷酸化MTOR（在S2159上）直接激活MTORC1和MTORC2信号。 此外，TBK1促进IFNB的生产的能力，ITYPE ITYEN启动一线主机防御 针对感染性微生物，需要MTOR S2159磷酸化和MTORC1活性。这项工作直接 链接的两个先前未知的信号系统在功能上相互作用。正如先前的工作报道，脂肪细胞 - 特定的TBK1基因敲除（KO）在小鼠中引起全身性胰岛素耐药性（MTOR的脂肪细胞特异性KO也是如此， 猛禽（MTORC1）或Rictor（MTORC2），我们决定研究TBK1-MTOR信号传导的潜在作用 代谢控制通过产生“抗TBK1” MTOR敲入小鼠等位基因，具有不可磷酸磷酸 Ala在S2159（MTORA）。我们的初步结果表明，饮食引起的肥胖（DIO）MTORA/A小鼠暴露于胰岛素 相对于DIO 控件。我们的中心假设认为TBK1-MTOR信号可防止胰岛素抵抗和 肥胖期间高血糖。特别是，我们假设脂肪组织中的TBK1-MTOR信号传导 促进脂肪细胞中的养分储存，并保护在 肥胖。因此，我们进一步假设脂肪细胞和巨噬细胞中的TBK1-MTORC1信号传导介导 DIO期间促进全身胰岛素敏感性和血糖控制的炎症反应。定义 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（AIM 1） 并定义TBK1-MTOR信号在控制先天免疫功能和血糖的巨噬细胞中的作用 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， 项目将增强我们对整合先天免疫和代谢反应的机制的理解 并防止与肥胖与II型糖尿病相关的糖尿病 - 揭示潜在的新治疗机会。