We found increased activation of MAPK/ERK, JAK2/STAT3, and PI3k/AKT signaling pathways in human leiomyoma cells as a result of adipocyte coculture, outlining the pathophysiological link between adipocyte hypertrophy in obesity and the development of uterine leiomyoma. Here, AKT1 is linked to obesity due to melanocortin 4 receptor deficiency.