Further mechanism study found that the expression of EDA in mouse liver was regulated by peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor (RXR)-α, which further promoted c-Jun N-terminal kinase (JNK) activation and inhibited the serine phosphorylation of IRS1 in skeletal muscle, resulting in impaired insulin sensitivity of skeletal muscle in obesity. The gene discussed is MAPK8; the disease is obesity due to melanocortin 4 receptor deficiency.