In contrast to in these in vitro findings, in vivo knockout strategies failed to elucidate the metabolic role of this protein, since mice lacking Pnpla3 generated by two independent groups displayed no metabolic and phenotypical alterations, even not when challenged with several metabolic insults (i.e., refeeding, high-sucrose diet, diet-induced obesity, methionine-choline deficient diet or leptin deficiency background) [32,33]. This evidence concerns the gene PNPLA3 and obesity due to melanocortin 4 receptor deficiency.