Taken together, inflammatory mediators, hyperinsulinemia, and elevated glucose levels during obesity-induced insulin resistance likely intersect to synergistically upregulate ATX expression and secretion from adipose tissue in a feed-forward mechanism, thereby increasing circulating ATX and LPA levels, which may further enhance inflammation and insulin resistance (Figure 1). Here, ENPP2 is linked to obesity due to melanocortin 4 receptor deficiency.