-Ovariectomy (OVX) increases body weight and body fat in female mice (76, 83, 84, 262–264).-OVX improves HFD-induced insulin resistance in female mice (75).-OVX of ERα mice led to decreased body weight vs. sham-operated ERα mice (91).-Castration indirectly reduces estrogen in male mice, leading to enhanced adiposity and pronounced diet-induced obesity (72). Here, ESR1 is linked to obesity due to melanocortin 4 receptor deficiency.