Systems Biology Will Direct Vascular-Targeted Therapy for Obesity

Healthy adipose tissue expansion and metabolism during weight gain require coordinated angiogenesis and lymphangiogenesis. These vascular growth processes rely on the vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFRs). Several studies have shown that controlling vascular growth by regulating VEGF:VEGFR signaling can be beneficial for treating obesity; however, dysregulated angiogenesis and lymphangiogenesis are associated with several chronic tissue inflammation symptoms, including hypoxia, immune cell accumulation, and fibrosis, leading to obesity-related metabolic disorders. An ideal obesity treatment should minimize adipose tissue expansion and the advent of adverse metabolic consequences, which could be achieved by normalizing VEGF:VEGFR signaling. Toward this goal, a systematic investigation of the interdependency of vascular and metabolic systems in obesity and tools to predict personalized treatment ranges are necessary to improve patient outcomes through vascular-targeted therapies. Systems biology can identify the critical VEGF:VEGFR signaling mechanisms that can be targeted to regress adipose tissue expansion and can predict the metabolic consequences of different vascular-targeted approaches. Establishing a predictive, biologically faithful platform requires appropriate computational models and quantitative tissue-specific data. Here, we discuss the involvement of VEGF:VEGFR signaling in angiogenesis, lymphangiogenesis, adipogenesis, and macrophage specification - key mechanisms that regulate adipose tissue expansion and metabolism. We then provide useful computational approaches for simulating these mechanisms, and detail quantitative techniques for acquiring tissue-specific parameters. Systems biology, through computational models and quantitative data, will enable an accurate representation of obese adipose tissue that can be used to direct the development of vascular-targeted therapies for obesity and associated metabolic disorders.