The therapeutic potential of the adiponectin pathway

Adiponectin is an adipocyte-derived hormone that has been shown to play an important role in the regulation of metabolic, inflammatory, and apoptotic pathways. Adiponectin improves insulin sensitivity, promotes vascular health, and increases cell survival. These observations suggest a potential therapeutic role for adiponectin in the treatment of diabetes mellitus, cardiovascular diseases, and cancer. However, biologically active recombinant adiponectin proteins are inherently unstable and difficult to produce, thus making it a challenge for both research and clinical development. One main challenge relates to the existence of adiponectin as homo-/hetero-trimers, and complexes containing multiple adiponectin trimer units, in plasma. The underlying mechanism for adiponectin function is also not completely understood. Two receptors for adiponectin (ADIPOR1 and ADIPOR2) have been cloned, and activation of adenosine monophosphate-activated kinase (AMPK) has been reported to be downstream of the receptors. Recent findings suggest that adiponectin potently stimulates ceramidase activity via activation of its two known receptors, therefore connecting sphingolipid metabolism to adiponectin functions and providing a potential mechanism explaining the different actions of adiponectin. Interestingly, a new report also identified a pathway involving adiponectin and insulin receptor substrate 2, which is independent of the ADIPOR1/ADIPOR2 pathway. In this manuscript, we will review previous approaches and challenges in exploring adiponectin-based therapeutics. In particular, we will review some of the recent developments in engineering adiponectin proteins as well as potential therapeutic opportunities offered by recently elucidated adiponectin-mediated signaling pathways.