Enhancing metabolic action of FGF21 through adipocyte Connexin43 gap junction channels

项目总结/摘要 肥胖和2型糖尿病（T2 D）患者仍然需要具有增强疗效和改善安全性的治疗方法。 脂肪组织是治疗肥胖和T2 D的有希望的靶点。然而，药物制剂通常不能 由于脂肪细胞的巨大尺寸和血管化不足， 肥胖受试者。我们以前的工作表明，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在多个细胞之间共享有限的交感神经元输入。我们最近 发表揭示了连接蛋白43间隙连接通道激活剂达奈肽显著增强了 脂肪细胞偶联和成纤维细胞生长因子21（FGF 21）的代谢功效。初步工作表明， 脂肪细胞特异性Cx43过表达增强了FGF 21对体重减轻和改善肥胖的功效。 代谢，在很大程度上概括了达那肽对FGF 21的增强作用。根据我们初步的 数据和文献，我们提出了一个层次和协调的“点火燃烧”模型，FGF 21 参与大脑和脂肪组织来调节全身代谢。增强Cx43间隙连接 脂肪细胞之间的相互作用促进了来自大脑的FGF 21激活的交感神经信号的传播， 脂肪细胞的自主FGF 21信号。由于Klb在脑中的低表达，我们假设脑通常 获得足够的FGF 21输入。相比之下，脂肪组织，特别是来自肥胖受试者的脂肪组织， 受神经支配且对FGF 21刺激的细胞应答不敏感。几种新的小鼠模型和FGF 21 类似物的开发，我们建议（A）了解脂肪细胞Cx43的间隙连接的重要性， （B）测试“点燃-燃烧”模型，以及 增强脂肪组织中的“燃烧”在改善FGF 21功效方面的重要性。我们还将测试 (C)一种正交的，逐步的方法来实现Cx43间隙连接和FGF 21双重激动， 脂肪组织总之，这些研究将为FGF 21如何协调多种细胞因子提供新的见解。 器官调节能量消耗以及靶向脂肪组织间隙连接如何增强脂肪 组织药物参与。在这个过程中，我们还将产生几种新的FGF 21类似物， 作为肥胖症和T2 D的潜在疗法进行测试。

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.