Here we show that blockade of NF-κB mainly in liver, which is a key transcription factor involved in the regulation of gene expression in cytokines and pathways associated with inflammation, prevented HFD/obesity-induced hepatic steatosis, glucose intolerance, and abrogated insulin resistance in liver and systemic. This evidence concerns the gene NFKB1 and obesity due to melanocortin 4 receptor deficiency.