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.

项目摘要/摘要 肥胖和2型糖尿病患者（T2D）患者仍需要提高效率和提高安全性治疗。 脂肪组织是治疗肥胖和T2D的承诺靶标。但是，药物通常失败 有效地吸引脂肪细胞，因为它们的大小和血管不足，尤其是在 肥胖的受试者。我们以前的工作表明Connexin43（CX43）间隙连接被激活并诱导为 连接相邻的脂肪细胞，在多个细胞中共享有限的交感神经输入。我们的最新消息 出版物表明，connexin43间隙连接通道激活剂DaneGaptide显着增强 成纤维细胞生长因子21（FGF21）的脂肪细胞耦合和代谢效率。显示的初步工作 脂肪细胞特异性CX43过表达增强了FGF21的体重减轻和改善的效率 代谢，在很大程度上概括了DaneGaptide对FGF21的增强作用。基于我们的初步 数据和文献，我们提出了一个层次结构和协调的“点火燃烧”模型，通过该模型FGF21 增强CX43间隙连接 脂肪细胞之间有助于从大脑中传播FGF21激活的交感神经信号 脂肪细胞的自主FGF21信号。由于大脑中的KLB表达低，我们通常假设大脑 接收足够的FGF21输入。相反，脂肪组织，尤其是来自肥胖受试者的脂肪组织不足 对FGF21刺激的细胞反应的支配和难治性。有几种新的鼠标模型和FGF21 开发了类似物，我们建议（a）了解脂肪细胞CX43的重要性 频道功能在增强FGF21的代谢益处，（b）测试“点火燃烧”模型，并 在提高FGF21的效率方面增强脂肪组织中“燃烧”的重要性。我们还将测试 （c）实现CX43差距和FGF21双重激动剂的正交，逐步的方法 脂肪组织。总之，这些研究将提供有关FGF21如何坐标多个的新见解 器官调节能量支出以及靶向脂肪组织间隙连接的靶向如何增强脂肪 组织药物参与。在此过程中，我们还将生成几个新的FGF21类似物 被视为肥胖和T2D的潜在疗法。