The fibronectin type III domain containing 5 (FNDC5)/Irisin, a novel energy-regulating hormone, is associated with lipid and carbohydrate metabolism. It is produced in low amounts by normal hepatic tissue, while in human hepatocellular carcinoma (HCC), in which aberrant de novo lipogenesis (DNL) occurs, HCC-liver tissue over-expressed FNDC5/Irisin in association with gene expression of mediators involved in lipogenesis, inflammation and cancer, suggesting a possible protective role of the hormone from the liver damage. Irisin is secreted by skeletal muscle during exercise and influences energy and metabolic homeostasis. This hormone is a cleaved and secreted fragment of fibronectin type III domain-containing 5 (FNDC5). Elucidation of the FNDC5 gene regulation mechanism is necessary to clarify the function of irisin as a potential therapeutic target in human metabolic diseases. FNDC5/irisin, has recently been identified as a novel protein that stimulates the "browning" of white adipose by inducing thermogenesis via increased uncoupling protein 1 (UCP1). Increased FNDC5 in adipose and skeletal muscle may be a compensatory mechanism to offset high fat diet-induced weight gain and insulin resistance by increasing energy expenditure. That FNDC5 and its protein product Irisin are therapeutic targets for obesity-associated disorders.