Major findings of this study are (1) adipose tissue HDAC9 expression was increased in an HFD-induced mouse model of obesity and positively correlated with BMI in humans, (2) in female HFD-fed mice, adipocyte-specific HDAC9 gene deletion led to reduced weight gain and adipocyte hypertrophy, and improvements in glucose tolerance and insulin sensitivity, despite similar locomotor activity and food consumption. The gene discussed is INS; the disease is obesity due to melanocortin 4 receptor deficiency.