Studies in rodent models have indicated that the expression of ceramide biosynthetic genes increase in obesity and that interventions to reduce ceramide synthesis either by genetic modification (e.g., ablation of Sptlc2 [23, 24], Degs1 [12, 25], CerSs [26–28]) or pharmacological intervention (e.g., SPT inhibition using Myriocin [12, 29–31] or L-cycloserine [32], DES inhibition using Fenretinide [33], CerS1 inhibition using P053 [34], CerS6 depletion using antisense oligonucleotides (ASO) [35]) can ameliorate high-fat diet-induced metabolic dysfunction. Here, CERS1 is linked to obesity due to melanocortin 4 receptor deficiency.