In our study, we show that α-MSH and desacetyl-α-MSH are required for sexually dimorphic HF diet–induced C57BL/6J mouse obesity and, by association, α-MSH and desacetyl-α-MSH are required for female mice sensing a high-caloric diet and triggering adaptive thermogenesis. Here, POMC is linked to obesity due to melanocortin 4 receptor deficiency.