The following general issues could be considered as critical for NAFLD/NASH progression: (i) Obesity by itself has been reported to be able to trigger hypoxia in adipose tissue and the small intestine; in turn, the raising of hypoxic conditions in these tissues can result, through the action of HIF-1α and HIF-2α, in major and adverse metabolic effects, which include the development of insulin resistance and NAFLD. This evidence concerns the gene EPAS1 and obesity due to melanocortin 4 receptor deficiency.