Enhancing metabolic action of FGF21 through adipocyte Connexin43 gap junction channels

点击翻译按钮获取中文摘要

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.