Conjugated Linoleic Acid Promotes Human Adipocyte Insulin Resistance through NF?B-dependent Cytokine Production

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Robin Hopkins, Researcher (Creator)
Michael K. McIntosh, L.S. Keker Excellence Professor (Creator)
Institution
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/

Abstract: 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-a was associated with the activation of nuclear factor ?B (NF?B) as evidenced by 1) phosphorylation of I?Ba, I?Ba kinase, and NF?B p65, 2) I?Ba degradation, and 3) nuclear translocation of NF?B. Pretreatment with selective NF?B 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 NF?B activation or depletion of NF?B by RNA interference using small interfering NF?B 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 NF?B 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.

Additional Information

Publication
Journal of Biological Chemistry, 280(46), 38445-38456
Language: English
Date: 2005
Keywords
linoleic acid, insulin resistance, cytokines, essential fatty acids, immune response