Mechanisms of adiponectin regulation and use as a pharmacological target.

Adiponectin is an insulin-sensitizing and anti-inflammatory fat cell hormone that has immense potential as a therapeutic target for a multitude of obesity-associated diseases, including type 2 diabetes, NASH and atherosclerosis (Chandran M, Phillips SA, Ciaraldi T, Henry RR: Adiponectin: more than just another fat cell hormone?Diabetes Care 2003, 26:2442-2450). The adiponectin gene is located in chromosome 3q27, a susceptibility locus for T2DM and metabolic disorders (Saito K, Tobe T, Minoshima S, Asakawa S, Sumiya J, Yoda M, Nakano Y, Shimizu N, Tomita M: Organization of the gene for gelatin-binding protein (GBP28). Gene 1999, 229:67-73). Increased circulating levels of adiponectin are associated with improvement in the metabolic syndrome and reductions are strongly predictive of diabetes risk (Li S, Shin HJ, Ding EL, van Dam RM: Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2009, 302:179-188. Extensive efforts have been made to understand how adiponectin levels can be elevated. The complex post-translational processing and secretion of adiponectin provides a rich area where pharmacologic manipulation may be developed to increase adiponectin levels in humans. Circulating adiponectin levels are increased by many commonly used drugs, such as statins, angiotensin converting enzyme (ACE) inhibitors, and thiazolidinediones (TZDs) providing an important opportunity to gain insight into the mechanisms underlying their effects. This review describes the cellular processes by which adiponectin is synthesized and secreted, current therapeutics known to affect this pathway and the potential for therapeutic manipulation in human subjects.