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 肥胖相关糖尿病是一种复杂的代谢紊乱，在全球范围内发病率不断增加。 保守的激酶mTOR（雷帕霉素的机制靶点），其包含两个 功能不同的多蛋白复合物（含有raptor的mTORC 1和含有rictor的mTORC 2）， 促进体内葡萄糖和脂质的体内平衡。mTOR作为一种保守的营养传感器， 各种各样的局部和系统信号来控制细胞代谢和细胞生长。mTOR功能异常 导致II型糖尿病和各种免疫紊乱（以及其他疾病）。尽管生理 mTOR的重要性，我们对mTOR调控和功能的基本理解存在重大差距， mTOR与其他信号系统合作以控制整合生理学。我们实验室最近的工作 （Bodur et al. 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TBK 1直接磷酸化mTOR（在S2159上）以激活mTORC 1和mTORC 2信号传导。 此外，TBK 1促进IFNb产生的能力，IFNb是一种启动一线宿主防御的I型干扰素， 针对感染性微生物，需要mTOR S2159磷酸化和mTORC 1活性。这项工作直接 连接两个以前不知道功能相互作用的信号系统。先前的研究报告指出，脂肪细胞- 特异性Tbk 1敲除（KO）在小鼠中引起全身性胰岛素抵抗（如同Mtor的脂肪细胞特异性KO， Raptor（mTORC 1）或Rictor（mTORC 2）），我们决定研究TBK 1-mTOR信号转导在 通过产生携带不可磷酸化的“TBK 1抗性”mTOR敲入小鼠等位基因的代谢控制 Ala在S2159（MtorA）处。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 抵抗、高胰岛素血症和高血糖症，尽管体重和肥胖相对于DIO无变化 对照我们的中心假设是TBK 1-mTOR信号传导可以保护胰岛素抵抗， 肥胖期间的高血糖症。具体来说，我们假设脂肪组织中的TBK 1-mTOR信号传导 促进脂肪细胞中的营养储存，并保护异位脂质沉积和胰岛素抵抗， 肥胖因此，我们进一步假设脂肪细胞和巨噬细胞中的TBK 1-mTORC 1信号传导介导抗- 在DIO期间，炎症反应促进全身胰岛素敏感性和血糖控制。以限定 脂肪细胞和巨噬细胞特异性TBK 1-mTOR信号在代谢控制中的作用，我们将确定 脂肪细胞TBK 1-mTOR信号传导促进肥胖期间葡萄糖稳态的机制（Aim 1） 并确定TBK 1-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TBK 1-mTOR信号在体内的生理作用外， 该项目将增强我们对整合先天免疫和代谢反应的机制的理解 并预防肥胖相关的II型糖尿病-揭示了潜在的新治疗机会。