• HFD increases prorenin levels in the plasma and hypothalamus.• HFD increases Ang II level in the hypothalamus; PRR deletion decreases Ang II levels in the hypothalamus.• PRR deletion attenuates obesity-induced hypertension and diabetes.• PRR deletion attenuates HFD-induced astrogliosis, and astrocytic and neuronal NF-κB p65 activation in the Arc. This evidence concerns the gene ATP6AP2 and obesity due to melanocortin 4 receptor deficiency.