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. Here, IRS1 is linked to obesity due to melanocortin 4 receptor deficiency.