Sialic Acid Modification of Adiponectin Is Not Required for Multimerization or Secretion but Determines Half-Life in Circulation

Richards, AA, Colgrave, ML, Zhang, JL, Webster, J, Simpson, F, Preston, E, Wilks, D, Hoehn, KL, Stephenson, M, Macdonald, GA, Prins, JB, Cooney, GJ, Xu, AM and Whitehead, JP (2009) Sialic Acid Modification of Adiponectin Is Not Required for Multimerization or Secretion but Determines Half-Life in Circulation. MOLECULAR ENDOCRINOLOGY, 24 1: 229-239. doi:10.1210/me.2009-0133


Author Richards, AA
Colgrave, ML
Zhang, JL
Webster, J
Simpson, F
Preston, E
Wilks, D
Hoehn, KL
Stephenson, M
Macdonald, GA
Prins, JB
Cooney, GJ
Xu, AM
Whitehead, JP
Title Sialic Acid Modification of Adiponectin Is Not Required for Multimerization or Secretion but Determines Half-Life in Circulation
Journal name MOLECULAR ENDOCRINOLOGY   Check publisher's open access policy
ISSN 0888-8809
Publication date 2009-10-23
Year available 2009
Sub-type Article (original research)
DOI 10.1210/me.2009-0133
Volume 24
Issue 1
Start page 229
End page 239
Total pages 11
Editor De Franc0, D. B.
Place of publication United States
Publisher The Endocrine Society
Collection year 2010
Language eng
Subject C1
110306 Endocrinology
110107 Metabolic Medicine
970111 Expanding Knowledge in the Medical and Health Sciences
970106 Expanding Knowledge in the Biological Sciences
920104 Diabetes
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 composition. 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. (Molecular Endocrinology 24: 229-239, 2010)
Keyword O-GLYCOSYLATION SITES
CONSERVED LYSINE RESIDUES
TYPE-2 DIABETES-MELLITUS
COLLAGENOUS DOMAIN
INSULIN-RESISTANCE
POSTTRANSLATIONAL MODIFICATIONS
LIVER-CIRRHOSIS
ADIPOSE-TISSUE
INFLAMMATION
PREDICTION
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Sun, 10 Jan 2010, 00:03:23 EST