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J. Biol. Chem., Vol. 281, Issue 11, 7253-7259, March 17, 2006

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Intracellular Trafficking and Secretion of Adiponectin Is Dependent on GGA-coated Vesicles^*

Linglin Xie, Daniel Boyle, Daniel Sanford, Philipp E. Scherer, Jeffrey E. Pessin^¶, and Silvia Mora¹

From the Division of Biology, Kansas State University, Manhattan, Kansas 66506, the Departments of Cell Biology and Medicine, and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, and the ^¶Department of Pharmacological Sciences, State University of New York (SUNY), Stony Brook, New York 11794

Adiponectin (Acrp30) is an insulin-sensitizing hormone produced and secreted exclusively by adipose tissue. Confocal fluorescent microscopy demonstrated the colocalization of adiponectin with the Golgi membrane markers p115, -COP, and the trans-Golgi network marker, syntaxin 6. Treatment of cells with brefeldin A redistributed adiponectin to the endoplasmic reticulum where it colocalized with the chaperone protein BIP and inhibited secretion of adiponectin demonstrating a requirement for a functional Golgi apparatus for adiponectin release. Confocal fluorescent microscopy also demonstrated a colocalization of endogenous adiponectin with that of expressed GGA1myc (Golgi-localizing -adaptin ear homology ARF-binding protein) but with no significant overlap between adiponectin and the GGA2myc or GGA3myc isoforms. Consistent with confocal fluorescent microscopy, transmission electron microscopy demonstrated the colocalization of GGA1 with adiponectin. Although GGA1 did not directly interact with the adiponectin protein, the adiponectin enriched membrane compartments of adipocyte were precipitated by a GST-GGA1 cargo binding domain (VHS) fusion protein but not with a GST-GGA2 VHS or GST-GGA3 VHS fusion proteins. Moreover, co-expression of adiponectin with a GGA1 dominant-interfering mutant (GGA1-VHS GAT domain) resulted in a marked inhibition of adiponectin secretion in both 3T3L1 adipocytes and HEK293 cells, whereas no inhibition was detected with the truncated mutants GGA2-VHSGAT or GGA3-VHSGAT. Moreover, co-expression of wild type GGA1 with adiponectin enhanced secretion of adiponectin. Interestingly, leptin secretion was unaffected by neither the wild type form or GGA1 mutant. Taken together these data demonstrate that the trafficking of adiponectin through its secretory pathway is dependent on GGA-coated vesicles.

Received for publication, October 18, 2005 , and in revised form, November 28, 2005.

^* This work was supported by Junior Faculty Award 1-04-JF-36 from the American Diabetes Association and National Institutes of Health Grants P20-RR-17708 (to S. M.), P-20-RR017686 (to the Confocal Microfluorometry and Microscopy Core at Kansas State University), and DK55811 and DK63332. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Biology, 231 Ackert Hall, Kansas State University, Manhattan, KS 66506. Tel.: 785-532-6517; Fax: 785-532-6653; E-mail: mora{at}ksu.edu.

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