These findings were the basis for elucidating the involvement of adipose tissue macrophages as direct modulators of metabolism, and led to the observations that the increased free fatty acids exposure in obesity promotes the polarization of macrophages resident in the adipose tissue toward a pro-inflammatory (M1-polarized) phenotype which can activate inflammatory pathways and impair insulin signaling (Hevener et al., 2007; Lumeng et al., 2007; Nguyen et al., 2007). This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.