In type 2-high, type 2-low, and obesity-related asthma endotypes, chronic hypoxia, HIF-1α stabilization, ORMDL3-ceramide signaling, and systemic metabolic stress converge to induce highly glycolytic, Th2/Th17-polarizing DCs in a lactate-rich, acidic microenvironment. This evidence concerns the gene ORMDL3 and obesity due to melanocortin 4 receptor deficiency.