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Adiponectin, a hormone produced and secreted by adipocytes, modulates a number of metabolic processes, including glucose regulation, homeostasis, and fatty acid catabolism. It plays an important role in the suppression of the metabolic derangements that may result in type 2 diabetes, atherosclerosis and non-alcoholic fatty liver disease. Posttranslational modifications such as hydroxylation and glycosylation are important for regulating the activity of adiponectin since they influence the formation of high active multimeric complexes. In this study we addressed the role of reversible phosphorylation in modulating the activity of adiponectin. We showed that adiponectin is phosphorylated in vitro by several kinases, among them casein kinase 1 delta (CK1δ). CK1δ preferentially phosphorylates adiponectin within the globular domain. The formation of multimeric adiponectin complexes was increased by phosphatase treatment in vitro. Furthermore, specific inhibition of CK1δ by IC261 promotes the formation of higher molecular weight (HMW) complexes in human adipocytes. In summary, our data provide evidence that adiponectin is a phosphoprotein. Its reversible phosphorylation, especially at sites targeted by CK1δ in vitro, provides another regulatory mechanism to modulate complex formation and activity of adiponectin. [ABSTRACT FROM AUTHOR]