INS and obesity due to melanocortin 4 receptor deficiency: Recently, studies have found that extracellular matrix remodeling could be an important mechanism mediating obesity and cardiometabolic outcomes such as insulin resistance32,33, metabolic syndrome34 and type 2 diabetes35, through generating (1) mechanical barriers for glucose and insulin transporting to liver and muscle, and (2) alternating integrin signaling that culminate in impaired insulin action33.