Using iTRAQ-based quantitative proteomics, 4D-label free quantitative proteomics, and multiple reaction monitoring-mass spectrometry (MRM-MS), we found that obesity led to an increase in the levels of extracellular matrix protein 1 (ECM1) in the circulating sEVs of human subjects with obesity and high-fat diet-induced obesity (DIO) mouse models. The gene discussed is ECM1; the disease is obesity due to melanocortin 4 receptor deficiency.