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J. Biol. Chem., Vol. 279, Issue 25, 26735-26747, June 18, 2004

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Conjugated Linoleic Acid Induces Human Adipocyte Delipidation

AUTOCRINE/PARACRINE REGULATION OF MEK/ERK SIGNALING BY ADIPOCYTOKINES^*

J. Mark Brown, Maria Sandberg Boysen, Soonkyu Chung, Olowatoyin Fabiyi, Ron F. Morrison, Susanne Mandrup, and Michael K. McIntosh¶

From the Department of Nutrition, University of North Carolina at Greensboro, Greensboro, North Carolina 27402-6170 and the Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense DK-5230, Denmark

Dietary conjugated linoleic acid (CLA) reduces body fat in animals and some humans. Here we show that trans-10, cis-12 CLA, but not cis-9, trans-11 CLA, when added to cultures of stromal vascular cells containing newly differentiated human adipocytes, caused a time-dependent decrease in triglyceride content, insulin-stimulated glucose and fatty acid uptake, incorporation into lipid, and oxidation compared with controls. In parallel, gene expression of peroxisome proliferator-activated receptor- and many of its downstream targets were diminished by trans-10, cis-12 CLA, whereas leptin gene expression was increased. Prior to changes in gene expression and metabolism, trans-10, cis-12 CLA caused a robust and sustained activation of mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) signaling. Furthermore, the trans-10, cis-12 CLA-mediated activation of MEK/ERK could be attenuated by pretreatment with U0126 and pertussis toxin. In parallel, pretreatment with U0126 blocked the ability of trans-10, cis-12 CLA to alter gene expression and attenuate glucose and fatty acid uptake of the cultures. Intriguingly, the induction by CLA of MEK/ERK signaling was linked to hypersecretion of adipocytokines interleukin-6 and interleukin-8. Collectively, these data demonstrate for the first time that trans-10, cis-12 CLA decreases the triglyceride content of newly differentiated human adipocytes by inducing MEK/ERK signaling through the autocrine/paracrine actions of interleukins-6 and 8.

Received for publication, February 17, 2004 , and in revised form, March 25, 2004.

^* This work was supported by NIDDK/Office of Dietary Supplements, National Institutes of Health, Grant R01DK-63070 and North Carolina Agriculture Research Service Grant 06520 (to M. K. M.) and by the Danish Dairy Research Foundation and the Innovation Act under the Danish Government (to S. M.). 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.

^¶ To whom correspondence should be addressed: Dept. of Nutrition, 318 Stone Bldg., University of North Carolina at Greensboro, Greensboro, NC 27402-6170. Tel.: 336-256-0325; Fax: 336-334-4129; E-mail: mkmcinto{at}uncg.edu.

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