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A more recent version of this article appeared on November 18, 2005
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Papers In Press, published online ahead of print September 9, 2005
J. Biol. Chem, 10.1074/jbc.M508159200
Submitted on July 26, 2005
Revised on August 30, 2005
Accepted on September 9, 2005

Conjugated linoleic acid promotes human adipocyte insulin resistance through NFkappaB-dependent cytokine production

Soonkyu Chung, Jonathan Mark Brown, James Nathan Provo, Robin Hopkins, and Michael K. McIntosh

Nutrition Dept., University of North Carolina-Greensboro, Greensboro, NC 27402-6170

Corresponding Author: mkmcinto{at}uncg.edu

We previously demonstrated that trans-10, cis-12 conjugated linoleic acid (CLA) reduced the triglyceride (TG) content of human adipocytes by activating mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) signaling via interleukins-6 (IL-6) and 8 (IL-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’s isomer-specific induction of IL-6 and tumor necrosis factor-a (TNF-a) was associated with the activation of nuclear factor B (NFB) as evidenced by: 1) phosphorylation of IBa, IBa kinase (IKK), and NFB p65; 2) IBa 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’s suppression of insulin-stimulated glucose uptake at 24 h was associated with decreased total and plasma membrane glucose transporter 4 (Glut4) proteins. Inhibition of NFB activation or depletion of NFB by RNA interference using siNFB p65 attenuated CLA’s suppression of Glut4 and peroxisome proliferator activated receptor gamma (PPAR) 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 PPAR target gene expression and insulin sensitivity in mature human adipocytes.


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