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Journal of Lipid Research, Vol. 50, 225-232, February 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol^*

Arion Kennedy^*, Angel Overman^*, Kathleen LaPoint^*, Robin Hopkins^*, Tiffany West^*, Chia-Chi Chuang^*, Kristina Martinez^*, Doris Bell and Michael McIntosh^1,*

^* Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27402-6170
Cognis GmbH, Postflach 130164, D-40551, Dusseldorf, Germany

^* This work was supported by National Institutes of Health Grant 5R01 DK-063070-06, North Carolina Agriculture Research Service Grant NCARS 06771, and Cognis GmbH (M.M.), a fellowship award from the National Institutes of Health (F31DK076208), and the United Negro College Fund-Merck (A.K.).

Published, JLR Papers in Press, September 5, 2008.

¹ To whom correspondence should be addressed. e-mail: mkmcinto{at}uncg.edu

Inflammation plays a role in trans-10, cis-12 (10,12)-conjugated linoleic acid (CLA)-mediated delipidation and insulin resistance in adipocytes. Given the anti-inflammatory role of resveratrol (RSV), we hypothesized that RSV would attenuate inflammation and insulin resistance caused by 10,12 CLA in human adipocytes. RSV blocked 10,12 CLA induction of the inflammatory response by preventing activation of extracellular signal-related kinase and induction of inflammatory gene expression (i.e., IL-6, IL-8, IL-1β) within 12 h. Similarly, RSV suppressed 10,12 CLA-mediated activation of the inflammatory prostaglandin pathway involving phospholipase A₂, cyclooxygenase-2, and PGF₂. In addition, RSV attenuated 10,12 CLA increase of intracellular calcium and reactive oxygen species associated with cellular stress, and activation of stress-related proteins (i.e., activating transcription factor 3, JNK) within 12 h. 10,12 CLA-mediated insulin resistance and suppression of fatty acid uptake and triglyceride content were attenuated by RSV. Finally, 10,12 CLA-mediated decrease of peroxisome proliferator-activated receptor (PPAR) protein levels and activation of a peroxisome proliferator response element (PPRE) reporter were prevented by RSV. RSV increased the basal activity of PPRE, suggesting that RSV increases PPAR activity. Collectively, these data demonstrate for the first time that RSV prevents 10,12 CLA-mediated insulin resistance and delipidation in human adipocytes by attenuating inflammation and cellular stress and increasing PPAR activity.

Supplementary key words stress • anti-inflammatory • delipidation

Abbreviations: AMPK, AMP kinase; ATF3, activating transcription factor 3; [Ca⁺²]_i, intracellular calcium; CLA, conjugated linoleic acid; COX, cyclooxygenase; DCF, dichlorofluorescein; ER, endoplasmic reticulum; ERK, extracellular signal-related kinase; fluo-3 AM, fluo-3 acetoxymethyl ester; ISR, integrated stress response; JNK, c-Jun-NH2-terminal kinase; NFB, nuclear factor B; PG, prostaglandin; PLA₂, phospholipase A₂; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; ROS, reactive oxygen species; RSV, resveratrol; SIRT1, sirtuin 1; TG, triglyceride; TZD, thiazolidinedione; WAT, white adipose tissue

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