Title :
Sialic acid modification of
adiponectin is not required for multimerization or secretion but determines half-life in circulation
Abstract :
- Adiponectin is an adipocyte-secreted, insulin-sensitizing hormone the circulating levels of which are reduced in conditions of insulin resistance and diabetes
- Previous work has demonstrated the importance of posttranslational modifications, such as proline hydroxylation and lysine hydroxylation/glycosylation, in adiponectin oligomerization, secretion, and function
- Here we describe the first functional characterization of adiponectin sialylation
- Using a variety of biochemical approaches we demonstrated that sialylation occurs on previously unidentified O-linked glycans on Thr residues of the variable domain in human adiponectin
- Enzymatic removal of sialic acid or its underlying O-linked sugars did not affect adiponectin multimer com position
- Expression of mutant forms of adiponectin (lacking the modified Thr residues ) or of wild-type adiponectin in cells defective in sialylation did not compromise multimer formation or secretion, arguing against a structural role for this modification
- Activity of desialylated adiponectin was comparable to control adiponectin in L6 myotubes and acute assays in adiponectin (-/-) mice
- In contrast, plasma clearance of desialylated adiponectin was accelerated compared with that of control adiponectin , implicating a role for this modification in determining the half-life of circulating adiponectin
- Uptake of desialylated adiponectin by isolated primary rat hepatocytes was also accelerated, suggesting a role for the hepatic asialoglycoprotein receptor
- Finally, after chronic administration in adiponectin (-/-) mice steady-state levels of desialylated adiponectin were lower than control adiponectin and failed to recapitulate the improvements in glucose and insulin tolerance tests observed with control adiponectin
- These data suggest an important role for sialic acid content in the regulation of circulating adiponectin levels and highlight the importance of understanding mechanisms regulating adiponectin sialylation/desialylation