Enhancing metabolic action of FGF21 through adipocyte Connexin43 gap junction channels

项目摘要/摘要 肥胖和2型糖尿病(T2D)患者仍然需要提高疗效和改善安全性的治疗方法。 脂肪组织是治疗肥胖和T2D的有前途的靶点。然而，药理药剂通常会失败。 由于脂肪细胞的超大尺寸和血管生成不足，要有效地与其接触，特别是在 肥胖受试者。我们之前的工作表明，连接蛋白43(Cx43)间隙连接被激活并诱导 连接相邻的脂肪细胞，以便在多个细胞之间共享有限的交感神经元输入。我们最近 出版物显示，连接蛋白43缝隙连接通道激活剂danegapide显著增强 脂肪细胞偶联与成纤维细胞生长因子21的代谢效应。初步工作显示 脂肪细胞特异性Cx43过表达增强成纤维细胞生长因子21‘S减肥和改善体重的疗效 新陈代谢，很大程度上概括了丹奈肽对FGF21的增强作用。根据我们的初步调查 数据和文献，我们提出了一个分层和协调的“点火-燃烧”模型，通过该模型，FGF21 使大脑和脂肪组织参与调节全身新陈代谢。增强Cx43缝隙连接 脂肪细胞之间促进FGF21激活的交感信号从大脑和 脂肪细胞的自主FGF21信号。由于KLB在大脑中的低表达，我们通常假设大脑 接收足够的FGF21输入。相反，脂肪组织，特别是肥胖者的脂肪组织，是不够的。 神经支配，对FGF21刺激的细胞反应不敏感。有几个新的鼠标型号和FGF21 开发的类似物，我们建议(A)了解脂肪细胞Cx43‘S缝隙连接的重要性 通道功能在增强成纤维细胞生长因子21‘S代谢效益中的作用，(B)检验“点火-燃烧”模型，并 增强脂肪组织的“燃烧”对提高FGF21‘S疗效的重要性。我们还将测试 (C)一种正交的、分步实现Cx43缝隙连接和FGF21双重激动剂的方法 脂肪组织。总之，这些研究将为FGF21如何协调多个 调节能量消耗的器官以及靶向脂肪组织缝隙连接如何增强脂肪 组织药品合作。在这个过程中，我们还将生成几个新的FGF21类似物，它们可以 被测试为治疗肥胖症和T2D的潜在疗法。

PROJECT SUMMARY/ABSTRACT Obese and Type 2 diabetic (T2D) patients still need therapeutics with enhanced efficacy and improved safety. Adipose tissue is a promising target for treating obesity and T2D. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinary size and insufficient vascularization, especially in obese subjects. Our previous work suggests connexin43 (Cx43) gap junctions are activated and induced to connect neighboring adipocytes to share limited sympathetic neuronal inputs among multiple cells. Our recent publication reveals that danegaptide, a Connexin43 gap junction channel activator, significantly enhances adipocyte coupling and the metabolic efficacy of fibroblast growth factor 21 (FGF21). Preliminary work showed adipocyte-specific Cx43 overexpression enhanced FGF21’s efficacy on weight loss and improvement in metabolism, largely recapitulating the danegaptide’s potentiation effect on FGF21. Based on our preliminary data and literature, we propose a hierarchical and coordinated “ignition-combustion” model by which FGF21 engages the brain and adipose tissue to regulate systemic metabolism. Enhancing Cx43 gap junctions between adipocytes facilitates the dissemination of FGF21-activated sympathetic signals from the brain and adipocytes’ autonomous FGF21 signals. Due to low Klb expression in the brain, we postulate the brain usually receives sufficient FGF21 inputs. In contrast, adipose tissue, especially from obese subjects, is insufficiently innervated and refractory to FGF21-stimulated cellular response. With several new mouse models and FGF21 analogs developed, we propose to (A) understand the importance of the adipocyte Cx43’s gap junction channel function in enhancing FGF21’s metabolic benefits, (B) test the “ignition-combustion” model, and the importance of enhancing “combustion” in the adipose tissue in improving FGF21’s efficacy. We will also test (C) an orthogonal, step-by-step approach to achieving Cx43 gap junction and FGF21 dual agonism in the adipose tissue. Altogether, these studies will provide novel insights into how FGF21 coordinates multiple organs to regulate energy expenditure and how targeting adipose tissue gap junctions can enhance adipose tissue pharmaceutical engagement. In this process, we will also generate several new FGF21 analogs that can be tested as potential therapeutics for obesity and T2D.