To the Editor: We read with interest the review by Kaser et al. (1), focusing on treatment perspectives for non-alcoholic fatty liver disease (NAFLD). The authors suggest that adiponectin might be a promising target in NAFLD treatment in the future. Although we had previously supported this hypothesis (2,3), there are pivotal questions requiring answers prior to introducing adiponectin in clinical trials. In the liver, adiponectin increases insulin sensitivity and has antifibrogenic and anti-inflammatory effects (4). In a recent meta-analysis, serum adiponectin was similar between patients with simple steatosis and controls, but lower in patients with non-alcoholic steatohepatitis (NASH), indicating that hypoadiponectinemia possibly plays an important pathophysiological role in the progression from simple steatosis to NASH (5). There are three potential ways of intervention: increase in innate adiponectin expression and secretion through administration of various therapeutic agents and/or lifestyle modifications; administration of recombinant adiponectin; and administration of adiponectin analogues. Indirect increase in innate adiponectin has been previously reviewed (4). In brief, thiazolidinediones, statins, orlistat, sibutramine, rimonabant and/or lifestyle modifications seem to act, at least partly, by increasing circulating adiponectin. Recombinant adiponectin or adiponectin analogues have not as yet been administered in humans with NAFLD. However, recombinant adiponectin exerts hepatoprotective effect in mice with NASH (6,7). Furthermore, osmotin, a plant antifungal protein, has functional similarity to adiponectin and is a ligand for the yeast homologue of the adiponectin receptor (8), although its action on human adiponectin receptors remains to be elucidated. Nevertheless, there are some dilemmas. First, it is rather difficult to produce functionally active recombinant adiponectin. Extensive post-translational modifications (hydroxylation, glycosylation and disulphide bond formation) are required for efficient adiponectin multimerisation and secretion; succination inhibits the inappropriate multimerisation and secretion and sialylation reduces clearance from the circulation (9). Adiponectin analogues could provide alternatives to the complicated adiponectin post-translational modifications. Furthermore, it has been recently emphasised that causality between insulin resistance (IR) and hypoadiponectinemia in humans is not established. According to this concept, hypoadiponectinemia might be the consequence of IR (10). Data in favour of this argument support that: individuals with adiponectin gene mutations resulting in little or no circulating adiponectin may have normal IR; severe insulin deficiency seen in patients with type 1 diabetes mellitus is associated with high circulating adiponectin; genetic or acquired defects in the insulin receptor (receptoropathy) resulting in global IR are associated with elevated adiponectin; and insulin infusion in healthy individuals suppresses adiponectin in vivo (10). Likewise, circulating adiponectin in NASH-related cirrhosis increases (4), when IR is dramatically increased. The decreased hepatic clearance of adiponectin and/or a compensatory increase towards the overwhelming production of proinflammatory cytokines in cirrhosis are the most probable explanations. However, the inhibition of insulin suppression on adiponectin (10) or a potential harmful effect of adiponectin (11), when NAFLD progresses to cirrhosis, could not be excluded. In conclusion, there are data proposing adiponectin as a therapeutic target for patients with NAFLD. It is theoretically an appealing concept, but there are many issues that need to be elucidated before adiponectin could be used in clinical trials. S.A. Polyzos: Concept/design, drafting article, critical revision of article, approval of article. J. Kountouras: Concept/design, drafting article, critical revision of article, approval of article, supervision. C. Zavos: Design, critical revision of article, approval of article. None.