Our study elucidates Ces2a and CES2 as microsomal DAG and lysoPC hydrolases in vivo and suggests that aberrant hepatic lipid signaling due to decreased hepatic CES2/Ces2a expression is an important driver in the development of obesity-induced NAFLD and insulin resistance in humans and mice. This evidence concerns the gene CES2 and obesity due to melanocortin 4 receptor deficiency.