Our findings indicate that C16:0 ceramides derived from CerS6 promote organellar stress and cause alterations in mitochondrial morphology and function within hypothalamic neurons, ultimately contributing to impairments of metabolic control linked to diet-induced obesity, particularly through actions in SF-1- and POMC- but not AgRP-expressing cells. Here, AGRP is linked to obesity due to melanocortin 4 receptor deficiency.