This study is the first to prove that obesity potentiated ESCC growth and invasion with relation to the AMPK-YAP signal pathway and reveal that obesity downregulated AMPK and p-AMPK, while upregulating MMP9, total YAP, p-YAP, and nonphosphorylated YAP protein expression. Here, MMP9 is linked to obesity due to melanocortin 4 receptor deficiency.