The melanocortin pathway in the hypothalamus is essential for maintaining energy homeostasis and includes neurons in the arcuate nucleus and the paraventricular nucleus (PVN) of the hypothalamus. Diet-induced obesity (DIO) causes damage to the arcuate nucleus, which is more severe in male than in female mice. Single-minded 1 (Sim1) neurons in the PVN are essential for controlling energy homeostasis. Whether hypothalamic injury by DIO includes the PVN is not known. Here we tested whether DIO induces injury to Sim1 neurons of the PVN. In male and female mice, DIO induced injury to Sim1 neurons in the PVN and neuronal loss without local microglia activation. Differently, DIO induced neuronal loss and microglial activation in the arcuate nucleus of males, but not of the female. Thus, injury to Sim1 neurons of the PVN is a shared feature of hypothalamic damage by DIO in male and female mice, while injury to the arcuate nucleus is specific to male mice. The identity of the PVN neurons injured by DIO in the PVN of male and female mice is not known. Melanocortin-4 receptor (MC4R) is essential to control body weight. Sim1 neurons in PVN include neurons that express the MC4R (Sim1/MC4R neurons). DIO induced loss of MC4R protein and decreased mitochondria abundance in Sim1/MC4R neurons of male and female mice. In male but not female mice, DIO reduced the neurogenesis of Sim1/MC4R neurons. However, the number of Sim1/MC4R neurons was unchanged in the PVN of both male and female mice, while other, non-Sim1/MC4R neurons were decreased. Feeding male and female mice with DIO a low-fat diet reduced weight and recovered the abundance of MC4R protein in the Sim1/MC4R neurons, but the number of non-Sim1/MC4R neurons in the PVN remained decreased. Thus, Sim1/MC4R neurons in the PVN, but not other neurons at this location, are resistant to neuronal death by HF diet and can recover MC4R protein abundance after weight loss. Together, the data suggest that Sim1/MC4R neurons are a preferential target for anti-obesity therapy.