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

项目摘要/摘要 胰岛素是胰升糖素样肽-1(GLP-1)的类似物，改善2型糖尿病的血糖控制 并通过尚未完全了解的机制来对抗肥胖。我们的初步数据显示， 在糖尿病前期患者和小鼠中，GLP-1类似物治疗导致激活细胞因子IL-6的血浆水平增加 STAT3信号，诱导脂肪组织中棕色(米色)脂肪细胞分化(AT)。我们发现 血浆IL-6的诱导是通过刺激白细胞内的GLP-1受体(GLP-1R)发生的。有趣的是， 在啮齿动物中的研究表明，GLP-1/GLP-1R信号也可以诱导AT褐变。基于这些观察， 我们推测，胰岛素诱导AT褐变的部分原因是瞬时的IL-6/IL-6R/STAT3信号。我们的初选 目的是进一步阐明IL-6和GLP-1信号在介导有益代谢效应中的作用。 胰岛素疗法。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进行。 饮食诱导肥胖模型。将使用GLP-1类似物治疗结合IL-6封闭抗体。特定的 目的1是研究(A)胰岛素治疗对IL-6诱导/下游STAT3信号和AT褐变的影响 (B)验证小鼠作为研究胰岛素诱导的IL-6信号的模型作为一种 AT Browning的调解人。具体目的2是：(A)研究GLP-1类似物是否对米色脂肪生成有影响 依赖于人类脂肪细胞前体细胞中的IL-6信号；以及(B)研究GLP-1类似物是否对米色有影响 小鼠的脂肪生成依赖于IL-6信号。我们希望发现1)GLP-1模拟信号通过GLP-1 1R诱导白细胞分泌IL-6，2)GLP-1类似物治疗通过两者诱导脂肪组织褐化 GLP-1/GLP-1R直接信号转导和INT间接诱导的IL-6/IL-6R/STAT3信号转导。这样做的结果 新的研究将为GLP-1类似物的减肥机制提供关键的见解，并作为基础 为糖尿病和肥胖症开发更有针对性的治疗方法。了解IL-6的抗糖尿病作用将 对解释IL-6阻断的结果也很重要，IL-6阻断是糖尿病患者的一种治疗方法 以及其他炎症性疾病，可能需要重新考虑。

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.