Enhancing metabolic action of FGF21 through adipocyte Connexin43 gap junction channels

通过脂肪细胞 Connexin43 间隙连接通道增强 FGF21 的代谢作用

• 批准号: 10716136
• 负责人: Yi Zhu
• 金额: $ 46.19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716136
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agonists; Agonist; Body Weight decreased; Brain; Brain region; Brown Fat; Cells; Chemosensitization; Clinical Trials; Connexin 43; Connexins; Coupling; Data; Development; Diffusion; Energy Metabolism; Gap Junctions; Genetic Models; Hormones; Human; Hyperglycemia; Lipids; Literature; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Peripheral; Pharmacologic Substance; Process; Protein Isoforms; Proteins; Proteomics; Publications; Refractory; Respiration; Rodent; Safety; Serum; Signal Transduction; Testing; Therapeutic; Tissues; Triglycerides; Type 2 diabetic; Vascularization; Work; analog; blood glucose regulation; brain tissue; diabetic patient; fibroblast growth factor 21; gap junction channel; glycemic control; hydrophilicity; improved; insight; insulin sensitivity; metabolomics; mouse model; novel; obese patients; obese person; overexpression; pharmacologic; response; targeted agent

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.

项目概要/摘要 肥胖和 2 型糖尿病 (T2D) 患者仍然需要提高疗效和安全性的治疗方法。 脂肪组织是治疗肥胖和 T2D 的一个有希望的靶点，但是药物通常会失败。 由于脂肪细胞异常大且血管化不足，因此能够有效地参与脂肪细胞，特别是在 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在多个细胞之间共享有限的交感神经元输入。 该出版物揭示了 danegaptide（一种 Connexin43 间隙连接通道激活剂）可显着增强 初步工作表明脂肪细胞偶联和成纤维细胞生长因子 21 (FGF21) 的代谢功效。 脂肪细胞特异性 Cx43 过表达增强了 FGF21 的减肥功效和改善体重 代谢，主要概括了 danegaptide 对 FGF21 的增强作用。 根据数据和文献，我们提出了一种分层协调的“点火-燃烧”模型，其中 FGF21 参与大脑和脂肪组织调节全身代谢。 脂肪细胞之间的连接促进 FGF21 激活的大脑交感神经信号的传播 由于大脑中 Klb 表达较低，我们通常假设大脑存在脂肪细胞的自主 FGF21 信号。 相比之下，脂肪组织，尤其是来自肥胖受试者的脂肪组织，则缺乏足够的 FGF21 输入。 一些新的小鼠模型和 FGF21 对 FGF21 刺激的细胞反应具有神经支配和抵抗作用。 开发了类似物，我们建议 (A) 了解脂肪细胞 Cx43 间隙连接的重要性 通道功能增强 FGF21 的代谢益处，(B) 测试“点火-燃烧”模型，以及 我们还将测试增强脂肪组织“燃烧”对于提高 FGF21 功效的重要性。 (C) 一种正交的、逐步的方法来实现 Cx43 间隙连接和 FGF21 双重激动作用 总而言之，这些研究将为 FGF21 如何协调多个方面提供新的见解。 调节能量消耗的器官以及靶向脂肪组织间隙连接如何增强脂肪 在此过程中，我们还将生成几种新的 FGF21 类似物。 作为肥胖和 T2D 的潜在疗法进行测试。