The main findings from this study are that plasma dihydroceramide content is significantly greater in individuals with obesity with and without T2D, plasma ceramide and dihydroceramide content are negatively related to insulin sensitivity, and that dihydroceramide administration to myotubes decreased insulin sensitivity in vitro, consistent with a causal role in promoting whole-body insulin resistance. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.