GLP-1 Therapy: The Role of IL-6 Signaling and Adipose Tissue Remodeling in Metabolic Response

GLP-1 疗法：IL-6 信号传导和脂肪组织重塑在代谢反应中的作用

• 批准号: 9808679
• 负责人: Absalon Dennis Gutierrez
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808679
• 关键词: Adipocytes; Adipose tissue; Agonist; Antibodies; Antidiabetic Drugs; Antiinflammatory Effect; Biopsy; Blocking Antibodies; Blood Circulation; Brown Fat; Cell Culture Techniques; Cells; Chronic; Clinical Trials; Complex; Data; Diabetes Mellitus; Diet; Equilibrium; Future; GLP-I receptor; Glucose; Human; Inflammation; Inflammatory; Injections; Insulin Resistance; Interleukin Activation; Interleukin-6; Intervention; Leukocytes; Link; Measurement; Mediating; Mediator of activation protein; Metabolic; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Patients; Peripheral Blood Mononuclear Cell; Physiological; Plasma; Positron-Emission Tomography; Prediabetes syndrome; Process; Property; Publishing; Receptor Signaling; Rodent; Role; STAT3 gene; Signal Transduction; Source; Testing; Therapeutic; adipocyte differentiation; analog; base; blood glucose regulation; clinical investigation; cytokine; diabetes mellitus therapy; fluorodeoxyglucose; glucagon-like peptide 1; improved; insight; lipid biosynthesis; macrophage; mouse model; novel; preclinical study; progenitor; response; subcutaneous; targeted treatment; uptake

PROJECT SUMMARY/ABSTRACT Incretins, the analogs of glucagon-like peptide-1 (GLP-1), improve glucose control in type 2 diabetes mellitus and counteract obesity through mechanisms that are not completely understood. Our preliminary data show that, in prediabetic patients and mice, GLP-1 analog therapy induces an increase in plasma IL-6, a cytokine activating STAT3 signaling, which induces brown (beige) adipocyte differentiation in adipose tissue (AT). We discovered that plasma IL-6 induction occurs through GLP-1 receptor (GLP-1R) stimulation in leukocytes. Interestingly, studies in rodents indicate that GLP-1 / GLP-1R signaling also induces AT beiging. Based on these observations, we hypothesize that incretins induce AT browning in part via transient IL-6 / IL-6R / STAT3 signaling. Our primary objective is to further elucidate the role of IL-6 and GLP-1 signaling in mediating beneficial metabolic effects of incretin therapy. Our studies will be paralleled in a human clinical trial, a human cell culture model, and a mouse diet-induced obesity model. GLP-1 analog therapy combined with an IL-6 blocking antibody will be used. Specific Aim 1 is to (A) investigate IL-6 induction / downstream STAT3 signaling and AT browning upon incretin therapy in prediabetic human patients; and (B) validate mice as a model to study incretin-induced IL-6 signaling as a mediator of AT browning. Specific Aim 2 is to (A) investigate if GLP-1 analog effects on beige adipogenesis depend on IL-6 signaling in human adipocyte progenitors; and (B) investigate if GLP-1 analog effects on beige adipogenesis depend on IL-6 signaling in mice. We expect to discover that 1) GLP-1 analog signaling via GLP- 1R induces IL-6 secretion by leukocytes, and 2) GLP-1 analog therapy induces adipose tissue browning via both direct GLP-1 / GLP-1R signaling and indirect incretin-induced IL-6 / IL-6R / STAT3 signaling. The results of this novel study will give critical insights on the anti-obesity mechanisms of GLP-1 analogs and serve as the basis for developing more targeted therapies for diabetes and obesity. Understanding the anti-diabetic IL-6 effects will also be important for interpreting the results of IL-6 blockade, a therapeutic approach for patients with diabetes and other inflammatory conditions, which may need to be re-considered.

项目摘要/摘要 肠肠座，胰高血糖素样肽-1（GLP-1）的类似物改善2型糖尿病的葡萄糖对照 并通过未完全理解的机制来抵消肥胖。我们的初步数据表明， 在糖尿病前患者和小鼠中，GLP-1模拟疗法诱导血浆IL-6的增加，一种激活的细胞因子 STAT3信号传导，可诱导脂肪组织中的棕色（米色）脂肪细胞分化（AT）。我们发现了 血浆IL-6诱导通过白细胞中的GLP-1受体（GLP-1R）刺激发生。有趣的是， 在啮齿动物中的研究表明，GLP-1 / GLP-1R信号传导也会在诱导时诱导。基于这些观察， 我们假设泌乳素通过瞬态IL-6 / IL-6R / STAT3信号传导部分诱导褐变。我们的主要 目的是进一步阐明IL-6和GLP-1信号传导在中介有益代谢作用中的作用 肠染料素治疗。我们的研究将在人类临床试验，人类细胞培养模型和小鼠中平行 饮食引起的肥胖模型。将使用GLP-1模拟疗法与IL-6阻断抗体结合使用。具体的 AIM 1是（a）研究IL-6诱导 /下游STAT3信号传导以及肠降直直染蛋白治疗后的褐变 在糖尿病前患者中； （b）验证小鼠作为研究肠降血糖素诱导的IL-6信号作为A的模型 AT Browning的中介。特定目的2是（a）研究GLP-1模拟对米色脂肪形成是否影响 取决于人脂肪细胞祖细胞中的IL-6信号传导； （b）研究GLP-1模拟对米色的影响是否影响 脂肪形成取决于小鼠的IL-6信号传导。我们希望发现1）通过GLP-的GLP-1模拟信号传导 1R诱导白细胞诱导IL-6分泌，2）GLP-1模拟疗法通过两者都诱导脂肪组织褐变 直接GLP-1 / GLP-1R信号传导和间接肠降直直染蛋白诱导的IL-6 / IL-6R / STAT3信号传导。结果的结果 新的研究将对GLP-1类似物的抗肥胖机制提供关键的见解，并作为基础 用于开发更多针对糖尿病和肥胖症的靶向疗法。了解抗糖尿病IL-6效应将 对于解释IL-6封锁的结果也很重要，IL-6封锁的结果是糖尿病患者的治疗方法 以及其他可能需要重新考虑的炎症条件。