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Article: Sialic acid modification of adiponectin is not required for multimerization or secretion but determines half-life in circulation

TitleSialic acid modification of adiponectin is not required for multimerization or secretion but determines half-life in circulation
Authors
Issue Date2010
PublisherEndocrine Society. The Journal's web site is located at http://mend.endojournals.org/
Citation
Molecular Endocrinology, 2010, v. 24 n. 1, p. 229-239 How to Cite?
AbstractAdiponectin 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. Copyright © 2010 by The Endocrine Society.
Persistent Identifierhttp://hdl.handle.net/10722/125063
ISSN
2015 Impact Factor: 3.432
2015 SCImago Journal Rankings: 2.195
ISI Accession Number ID
Funding AgencyGrant Number
National Health and Medical Research Council of Australia
National Heart Foundation
Diabetes Australia Research Trust
Funding Information:

This work was supported by grants from the National Health and Medical Research Council of Australia ( to J.P.W., G. A. M., and J.B.P.), the National Heart Foundation ( to J.P.W.), and the Diabetes Australia Research Trust ( to A. A. R.).

References

 

DC FieldValueLanguage
dc.contributor.authorRichards, AAen_HK
dc.contributor.authorColgrave, MLen_HK
dc.contributor.authorZhang, Jen_HK
dc.contributor.authorWebster, Jen_HK
dc.contributor.authorSimpson, Fen_HK
dc.contributor.authorPreston, Een_HK
dc.contributor.authorWilks, Den_HK
dc.contributor.authorHoehn, KLen_HK
dc.contributor.authorStephenson, Men_HK
dc.contributor.authorMacdonald, GAen_HK
dc.contributor.authorPrins, JBen_HK
dc.contributor.authorCooney, GJen_HK
dc.contributor.authorXu, Aen_HK
dc.contributor.authorWhitehead, JPen_HK
dc.date.accessioned2010-10-31T11:09:21Z-
dc.date.available2010-10-31T11:09:21Z-
dc.date.issued2010en_HK
dc.identifier.citationMolecular Endocrinology, 2010, v. 24 n. 1, p. 229-239en_HK
dc.identifier.issn0888-8809en_HK
dc.identifier.urihttp://hdl.handle.net/10722/125063-
dc.description.abstractAdiponectin 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. Copyright © 2010 by The Endocrine Society.en_HK
dc.languageengen_HK
dc.publisherEndocrine Society. The Journal's web site is located at http://mend.endojournals.org/en_HK
dc.relation.ispartofMolecular Endocrinologyen_HK
dc.subject.meshAdiponectin - blood - chemistry - genetics - metabolism - secretion-
dc.subject.meshProtein Multimerization-
dc.subject.meshProtein Processing, Post-Translational-
dc.subject.meshSialic Acids - metabolism-
dc.subject.meshSialyltransferases - metabolism-
dc.titleSialic acid modification of adiponectin is not required for multimerization or secretion but determines half-life in circulationen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0888-8809&volume=24&issue=1&spage=229&epage=239&date=2010&atitle=Sialic+Acid+Modification+Of+Adiponectin+Is+Not+Required+For+Multimerization+Or+Secretion+But+Determines+Half-life+In+Circulationen_HK
dc.identifier.emailXu, A:amxu@hkucc.hku.hken_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.description.naturelink_to_OA_fulltexten_HK
dc.identifier.doi10.1210/me.2009-0133en_HK
dc.identifier.pmid19855092-
dc.identifier.scopuseid_2-s2.0-73549089483en_HK
dc.identifier.hkuros175931en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-73549089483&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume24en_HK
dc.identifier.issue1en_HK
dc.identifier.spage229en_HK
dc.identifier.epage239en_HK
dc.identifier.isiWOS:000273071800019-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridRichards, AA=7402299860en_HK
dc.identifier.scopusauthoridColgrave, ML=6602708526en_HK
dc.identifier.scopusauthoridZhang, J=35504391800en_HK
dc.identifier.scopusauthoridWebster, J=35772076600en_HK
dc.identifier.scopusauthoridSimpson, F=9335599600en_HK
dc.identifier.scopusauthoridPreston, E=36786680800en_HK
dc.identifier.scopusauthoridWilks, D=7005956451en_HK
dc.identifier.scopusauthoridHoehn, KL=7004327250en_HK
dc.identifier.scopusauthoridStephenson, M=35771659500en_HK
dc.identifier.scopusauthoridMacdonald, GA=24478485700en_HK
dc.identifier.scopusauthoridPrins, JB=35450732500en_HK
dc.identifier.scopusauthoridCooney, GJ=7005169731en_HK
dc.identifier.scopusauthoridXu, A=7202655409en_HK
dc.identifier.scopusauthoridWhitehead, JP=7202914128en_HK

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