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

项目总结/摘要 胰高血糖素样肽-1（GLP-1）类似物肠促胰岛素改善2型糖尿病患者的血糖控制 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类似物治疗诱导血浆IL-6增加， STAT 3信号传导，其诱导脂肪组织（AT）中的棕色（米色）脂肪细胞分化。我们发现 血浆IL-6诱导通过GLP-1受体（GLP-1 R）刺激白细胞发生。有趣的是， 在啮齿动物中的研究表明GLP-1 / GLP-1 R信号传导也诱导AT beiging。根据这些观察， 我们假设肠促胰岛素部分通过瞬时IL-6 / IL-6 R/STAT 3信号传导诱导AT布朗宁。我们的首要 目的是进一步阐明IL-6和GLP-1信号转导在介导有益的代谢效应中的作用， 肠促胰岛素治疗。我们的研究将在人体临床试验，人类细胞培养模型和小鼠中进行 饮食诱导的肥胖模型。将使用GLP-1类似物治疗联合IL-6阻断抗体。具体 目的1是（A）研究肠促胰岛素治疗后IL-6诱导/下游STAT 3信号传导和AT布朗宁 （B）验证小鼠作为研究肠降血糖素诱导的IL-6信号传导的模型， AT布朗宁的介体。具体目的2是（A）研究GLP-1类似物是否对米色脂肪形成有影响 依赖于人脂肪细胞祖细胞中的IL-6信号传导;和（B）研究GLP-1类似物是否对米色 在小鼠中脂肪形成依赖于IL-6信号传导。我们期望发现1）GLP-1类似物通过GLP-1信号传导， 1 R诱导白细胞分泌IL-6，2）GLP-1类似物治疗通过两种途径诱导脂肪组织布朗宁 直接GLP-1 / GLP-1 R信号传导和间接肠促胰岛素诱导的IL-6 / IL-6 R/STAT 3信号传导。的结果 一项新的研究将为GLP-1类似物的抗肥胖机制提供重要的见解，并作为基础。 用于开发针对糖尿病和肥胖症的更有针对性的疗法。了解IL-6的抗糖尿病作用将 对于解释IL-6阻断（糖尿病患者的治疗方法）的结果也很重要 以及其他炎症性疾病，这可能需要重新考虑。

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.