The panel on the left shows how MAGEL-2 participates in the biological pathway to keep appetite under balance. The panel on the right indicates the effect when MAGEL-2 is absent or silenced. Loss of MAGEL-2 causes change in ubiquitination of proteins in leptin receptor internalization pathway, with affected proteins outlined in red (right). Proteins are labeled as follows: leptin (L), leptin receptor (LR), SH2B1 (S), IRS4 (I), NECDIN (N), MAGEL-2 (M), phosphatidylinositol-3 kinase (PI3K), RNF41 (R), USP8 (U8), Stam1 (St). MAGEL-2 and NECDIN in combination regulate LR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of either of these proteins may uncouple LR from ubiquitination pathways, providing a mechanism for obesity in PWS.