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

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

Research output: Contribution to journalArticle

135 Citations (Scopus)

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-α was associated with the activation of nuclear factor κB (NFκB) as evidenced by 1) phosphorylation of IκBα, IκBαkinase, and NFκB p65, 2) IκBα degradation, and 3) nuclear translocation of NFκB. Pretreatment with selective NFκB 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 NFκB activation or depletion of NFκB by RNA interference using small interfering NFκB p65 attenuated CLA suppression of glucose transporter 4 and peroxisome proliferator-activated receptor γ proteins and glucose uptake. Collectively, these data demonstrate for the first time that trans-10, cis-12 CLA promotes NFκB 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 γ target gene expression and insulin sensitivity in mature human adipocytes.

Original languageEnglish (US)
Pages (from-to)38445-38456
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number46
DOIs
StatePublished - Dec 1 2005

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Conjugated Linoleic Acids
Adipocytes
Insulin Resistance
Interleukin-6
Insulin
Cytokines
Peroxisome Proliferator-Activated Receptors
Facilitative Glucose Transport Proteins
Chemical activation
Mitogen-Activated Protein Kinase Kinases
Stromal Cells
Interleukin-8
Gene expression
Blood Vessels
Phosphotransferases
Gene Expression
Glucose
Phosphorylation
Membrane Transport Proteins
Cell membranes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Conjugated linoleic acid promotes human adipocyte insulin resistance through NFκB-dependent cytokine production. / Chung, Soonkyu; Brown, J. Mark; Provo, J. Nathan; Hopkins, Robin; McIntosh, Michael K.

In: Journal of Biological Chemistry, Vol. 280, No. 46, 01.12.2005, p. 38445-38456.

Research output: Contribution to journalArticle

Chung, Soonkyu ; Brown, J. Mark ; Provo, J. Nathan ; Hopkins, Robin ; McIntosh, Michael K. / Conjugated linoleic acid promotes human adipocyte insulin resistance through NFκB-dependent cytokine production. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 46. pp. 38445-38456.
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