Although it cannot be ruled out that the absence of functional leptin receptor (Lepr) may influence the effects of ovariectomy and E2, similar results reported in non-genetic rodent models of obesity and diabetes (high-fat diet plus streptozotocin) and obese-diabetic humans suggest that Lepr absence is not required for the detrimental effects of E2 in a diabesity context [5,14,15,34]. Here, LEPR is linked to obesity due to melanocortin 4 receptor deficiency.