Here we tested the consequences of therapeutic silencing of Fsp27 using generation 2.0 antisense oligonucleotides (ASOs) in both a dietary [high-fat diet (HFD)] and a genetic (leptin-deficient ob/ob) model of obesity, hepatosteatosis, and insulin resistance (26–28). This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.