Physiologic downregulation of GLUT4 in the fasted state, pathologic downregulation in insulin-resistant states, or genetic knockout result in diminished glucose flux. The diminished glucose flux is sensed by the adipocyte, resulting in increased RBP4 secretion. Additionally, the diminished glucose flux may limit the ability to generate glycerol-3-phosphate via glycolysis. The adipocyte becomes reliant on glyceroneogenesis for glycerol-3-phosphate production, which may be limiting for fatty acid re-esterification and contribute to increased fatty acid release. G3P, glycerol-3-phosphate; PEP, phosphoenolpyruvate.