INS and obesity due to melanocortin 4 receptor deficiency: In obesity, the polarization state of macrophages is oriented towards M1 [46], a phenotype characterized by the secretion of several different cytokines, such as TNF-α, IL-1 β, etc. They can potentially cause IR locally, through paracrine mechanisms in the skeletal muscle and in the liver, through endocrine mechanisms [47,48,49] by decreasing the expression of molecules involved in the insulin signaling pathway [50], or by inhibiting the activation of Akt by biosynthesis of ceramide [51].