To better understand the role of gonadal hormones–NPY system interaction and hypothalamic microglia activity in the sex-specific susceptibility to obesity and associated disorders, in the present study we investigated the effect of the conditional inactivation of the Npy1r gene in the forebrain of sham (correctly cycling) and ovariectomized (ovx) female mice fed with a standard diet (SD) or with an HFD. The gene discussed is NPY1R; the disease is obesity due to melanocortin 4 receptor deficiency.