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J. Biol. Chem., Vol. 280, Issue 46, 38445-38456, November 18, 2005

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Conjugated Linoleic Acid Promotes Human Adipocyte Insulin Resistance through NFB-dependent Cytokine Production^*

Soonkyu Chung, J. Mark Brown, J. Nathan Provo, Robin Hopkins, and Michael K. McIntosh1

From the Department of Nutrition, University of North Carolina at Greensboro, Greensboro, North Carolina 27402-6170 and the Department of Pathology and Comparative Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina 27157

We previously demonstrated that trans-10, cis-12 conjugated linoleic acid (CLA) reduced the triglyceride content of human adipocytes by activating mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) signaling via interleukins (IL) 6 and 8. However, the upstream mechanism is unknown. Here we show that CLA increased (6 h) the secretion of IL-6 and IL-8 in cultures containing both differentiated adipocytes and stromal vascular (SV) cells, non-differentiated SV cells, and adipose tissue explants. CLA isomer-specific induction of IL-6 and tumor necrosis factor- was associated with the activation of nuclear factor B (NFB) as evidenced by 1) phosphorylation of IB, IB kinase, and NFB p65, 2) IB degradation, and 3) nuclear translocation of NFB. Pretreatment with selective NFB inhibitors and the MEK/ERK inhibitor U0126 blocked CLA-mediated IL-6 gene expression. Trans-10, cis-12 CLA suppression of insulin-stimulated glucose uptake at 24 h was associated with decreased total and plasma membrane glucose transporter 4 proteins. Inhibition of NFB activation or depletion of NFB by RNA interference using small interfering NFB p65 attenuated CLA suppression of glucose transporter 4 and peroxisome proliferator-activated receptor proteins and glucose uptake. Collectively, these data demonstrate for the first time that trans-10, cis-12 CLA promotes NFB activation and subsequent induction of IL-6, which are at least in part responsible for trans-10, cis-12 CLA-mediated suppression of peroxisome proliferator-activated receptor target gene expression and insulin sensitivity in mature human adipocytes.

Received for publication, July 26, 2005 , and in revised form, August 30, 2005.

^* This work was supported by the NIDDK Office of Dietary Supplements, National Institutes of Health Grant R01DK-63070 and North Carolina Agriculture Research Service Grant 06771 (to M. K. 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.

¹ 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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