Kienesberger et al. showed that the ENPP2-LPA axis is involved in obesity-induced insulin resistance in muscles, affecting mitochondrial respiration in differentiated myotubes (D’Souza et al., 2018), validating the previously suggested key role of ENPP2-LPA axis in healthy and obese adipose tissue (Ferry et al., 2003; Boucher et al., 2005; Federico et al., 2012). Here, ENPP2 is linked to obesity due to melanocortin 4 receptor deficiency.