We previously demonstrated that trans-10, cis-12 (10,12) conjugated linoleic acid (CLA) induced inflammation and insulin resistance in primary human adipocytes by activating nuclear factor κB (NFκB) and extracellular signal-related kinase (ERK) signaling. In this study, we demonstrated that the initial increase in intracellular calcium ([Ca2+]i) mediated by 10,12 CLA was attenuated by TMB-8, an inhibitor of calcium release from the endoplasmic reticulum (ER), by BAPTA, an intracellular calcium chelator, and by D609, a phospholipase C (PLC) inhibitor. Moreover, BAPTA, TMB-8, and D609 attenuated 10,12 CLA–mediated production of reactive oxygen species (ROS), activation of ERK1/2 and cJun-NH2-terminal kinase (JNK), and induction of inflammatory genes. 10,12 CLA–mediated binding of NFκB to the promoters of interleukin (IL)-8 and cyclooxygenase (COX)-2 and induction of calcium-calmodulin kinase II (CaMKII) β were attenuated by TMB-8. KN-62, a CaMKII inhibitor, also suppressed 10,12 CLA–mediated ROS production and ERK1/2 and JNK activation. Additionally, KN-62 attenuated 10,12 CLA induction of inflammatory and integrated stress response genes, increase in prostaglandin F2α, and suppression of peroxisome proliferator activated receptor γ protein levels and insulin-stimulated glucose uptake. These data suggest that 10,12 CLA increases inflammation and insulin resistance in human adipocytes, in part by increasing [Ca2+]i levels, particularly calcium from the ER. We previously demonstrated that trans-10, cis-12 (10,12) conjugated linoleic acid (CLA) induced inflammation and insulin resistance in primary human adipocytes by activating nuclear factor κB (NFκB) and extracellular signal-related kinase (ERK) signaling. In this study, we demonstrated that the initial increase in intracellular calcium ([Ca2+]i) mediated by 10,12 CLA was attenuated by TMB-8, an inhibitor of calcium release from the endoplasmic reticulum (ER), by BAPTA, an intracellular calcium chelator, and by D609, a phospholipase C (PLC) inhibitor. Moreover, BAPTA, TMB-8, and D609 attenuated 10,12 CLA–mediated production of reactive oxygen species (ROS), activation of ERK1/2 and cJun-NH2-terminal kinase (JNK), and induction of inflammatory genes. 10,12 CLA–mediated binding of NFκB to the promoters of interleukin (IL)-8 and cyclooxygenase (COX)-2 and induction of calcium-calmodulin kinase II (CaMKII) β were attenuated by TMB-8. KN-62, a CaMKII inhibitor, also suppressed 10,12 CLA–mediated ROS production and ERK1/2 and JNK activation. Additionally, KN-62 attenuated 10,12 CLA induction of inflammatory and integrated stress response genes, increase in prostaglandin F2α, and suppression of peroxisome proliferator activated receptor γ protein levels and insulin-stimulated glucose uptake. These data suggest that 10,12 CLA increases inflammation and insulin resistance in human adipocytes, in part by increasing [Ca2+]i levels, particularly calcium from the ER. Obesity and its comorbidities are the most prevalent metabolic diseases in the US, affecting over 30% of the adult population (1.Centers for Disease Control and Prevention. US Obesity Trends, 1985–2006. Accessed 2007 at http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/index.htm.Google Scholar). Conjugated linoleic acid (CLA), dienoic isomers of linoleic acid, is one potential treatment for obesity. Animal (2.Kennedy A. Martinez K. Schmidt S. Mandrup S. Lapoint K. McIntosh M. Anti-obesity mechanisms of action of conjugated linoleic acid.J. Nutr. Biochem. 2009; 21: 171-179Crossref PubMed Scopus (199) Google Scholar) and human studies (3.Whigham L.D. Watras A.C. Schoeller D.A. Efficacy of conjugated linoleic acid for reducing fat mass: a meta-analysis in humans.Am. J. Clin. Nutr. 2007; 85: 1203-1211Crossref PubMed Scopus (267) Google Scholar) have demonstrated that supplementation with trans-10, cis-12 (10,12) CLA alone or in a mixture with the cis-9, trans-11 (9,11) isomer reduces body weight and fat deposition. 10,12 CLA has been shown to suppress the mRNA and protein levels of peroxisome proliferator activated receptor γ (PPARγ), the master regulator of adipogenesis, in murine 3T3-L1 adipocytes (4.Granlund L. Juvet L.K. Pedersen J.I. Nebb H.I. Trans10, cis12-conjugated linoleic acid prevents triacylglycerol accumulation in adipocytes by acting as a PPARgamma modulator.J. Lipid Res. 2003; 44: 1441-1452Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar) and cultures of newly differentiated human adipocytes (5.Brown J.M. Boysen M.S. Chung S. Fabiyi O. Morrison R.F. Mandrup S. McIntosh M.K. Conjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines.J. Biol. Chem. 2004; 279: 26735-26747Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). Our research group has reported that 10,12 CLA, but not 9,11 CLA, inhibited human preadipocyte differentiation (6.Brown J.M. Boysen M.S. Jensen S.S. Morrison R.F. Storkson J. Lea-Currie R. Pariza M. Mandrup S. McIntosh M.K. Isomer-specific regulation of metabolism and PPARgamma signaling by CLA in human preadipocytes.J. Lipid Res. 2003; 44: 1287-1300Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar) and caused delipidation of newly differentiated human adipocytes (5.Brown J.M. Boysen M.S. Chung S. Fabiyi O. Morrison R.F. Mandrup S. McIntosh M.K. Conjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines.J. Biol. Chem. 2004; 279: 26735-26747Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). Isomer-specific delipidation of adipocytes by CLA was due largely to a decrease in adipogenic/lipogenic gene expression, uptake of glucose and fatty acids, and triglyceride (TG) synthesis as opposed to an increase in oxidation (5.Brown J.M. Boysen M.S. Chung S. Fabiyi O. Morrison R.F. Mandrup S. McIntosh M.K. Conjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines.J. Biol. Chem. 2004; 279: 26735-26747Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 7.Chung S. Brown J.M. Provo J.N. Hopkins R. McIntosh M.K. Conjugated linoleic acid promotes human adipocyte insulin resistance through NFkappaB-dependent cytokine production.J. Biol. Chem. 2005; 280: 38445-38456Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). Interestingly, 10,12 CLA suppression of glucose and fatty acid uptake was dependent on activation of mitogen-activated protein kinase/extracellular kinase signal-regulated kinase (MEK/ERK) and nuclear factor κB (NFκB) signaling, as well as robust secretion or expression of the proinflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)α (5.Brown J.M. Boysen M.S. Chung S. Fabiyi O. Morrison R.F. Mandrup S. McIntosh M.K. Conjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines.J. Biol. Chem. 2004; 279: 26735-26747Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 7.Chung S. Brown J.M. Provo J.N. Hopkins R. McIntosh M.K. Conjugated linoleic acid promotes human adipocyte insulin resistance through NFkappaB-dependent cytokine production.J. Biol. Chem. 2005; 280: 38445-38456Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 9.Chung S. Brown J.M. Sandberg M.B. McIntosh M. Trans-10,cis-12 CLA increases adipocyte lipolysis and alters lipid droplet-associated proteins: role of mTOR and ERK signaling.J. Lipid Res. 2005; 46: 885-895Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). Consistent with these in vitro data, CLA supplementation in humans is associated with hyperglycemia, dyslipidemia, insulin resistance, and elevated levels of inflammatory prostaglandins (PG) and cytokines (10.Basu S. Riserus U. Turpeinen A. Vessby B. Conjugated linoleic acid induces lipid peroxidation in men with abdominal obesity.Clin. Sci. 2000; 99: 511-516Crossref PubMed Scopus (98) Google Scholar, 11.Riserus U. Basu S. Jovinge S. Fredrikson G.N. Arnlov J. Vessby B. Supplementation with conjugated linoleic acid causes isomer-dependent oxidative stress and elevated C-reactive protein: a potential link to fatty acid-induced insulin resistance.Circulation. 2002; 106: 1925-1929Crossref PubMed Scopus (267) Google Scholar, 12.Riserus U. Arner P. Brismar K. Vessby B. Treatment with dietary trans10cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome.Diabetes Care. 2002; 25: 1516-1521Crossref PubMed Scopus (368) Google Scholar, 13.Tholstrup T. Raff M. Straarup E. Lund P. Bruun J. Basur S. Opposing effects of trans-10, cis-12 conjugated linoleic acid and cis-9, trans-11 conjugated linoleic acid on risk markers for coronary heart disease.FASEB J. 2007; 21: A728Crossref Google Scholar). However, the upstream mechanism(s) by which 10,12 CLA induces inflammation, insulin resistance, and adipocyte delipidation remain unclear. One possible upstream mediator of CLA-induced inflammation and insulin resistance is intracellular calcium ([Ca2+]i), which is a vital second messenger for the activation of proteins involved in adipocyte proliferation, differentiation, and metabolism (14.Zemel M.B. Nutritional and endocrine modulation of intracellular calcium: implications in obesity, insulin resistance and hypertension.Mol. Cell. Biochem. 1998; 188: 129-136Crossref PubMed Scopus (174) Google Scholar). Elevated levels of [Ca2+]i have been reported to activate NFκB (15.Martin L. Pingle S.C. Hallam D.M. Rybak L.P. Ramkumar V. Activation of the adenosine A3 receptor in RAW 264.7 cells inhibits lipopolysaccharide-stimulated tumor necrosis factor-alpha release by reducing calcium-dependent activation of nuclear factor-kappaB and extracellular signal-regulated kinase 1/2.J. Pharmacol. Exp. Ther. 2006; 316: 71-78Crossref PubMed Scopus (92) Google Scholar, 16.Jeong H.J. Hong S.H. Park R.K. An N.H. Kim H.M. 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J.M. of of preadipocyte differentiation by prostaglandin PubMed Scopus Google Scholar). the of the role of [Ca2+]i in signaling, and adipocyte differentiation, we that [Ca2+]i is an upstream mediator of 10,12 inflammation and insulin resistance in human In this study, we demonstrated for the that CLA increases [Ca2+]i levels, to the production of reactive oxygen species (ROS), cJun-NH2-terminal kinase (JNK), and the induction of inflammatory and and insulin resistance in human were from was from and were from for was from and and ERK1/2 were from Cell was from of CLA were from acid and were from and were from acid was from and were from was with from the at the of at and of and the of and with a body was cells were as previously (5.Brown J.M. Boysen M.S. Chung S. Fabiyi O. Morrison R.F. Mandrup S. McIntosh M.K. Conjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines.J. Biol. Chem. 2004; 279: 26735-26747Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). newly differentiated human adipocytes were on of the differentiation was at a mixture of cells from or cells were by at the of were to in with and differentiation, cells were with and in with and human for the was with the differentiation and These cells were for the on of the primary human adipocytes were in and differentiated for was to and for cells were with at for and with for were with and was in a with an of were levels of We [Ca2+]i levels cells were with and an at for in the were with a of and which prevents from was a were with CLA TMB-8, BAPTA, or and was at for was and was at in the of calcium-dependent to were over are was as previously S. Brown J.M. Provo J.N. Hopkins R. McIntosh M.K. Conjugated linoleic acid promotes human adipocyte insulin resistance through NFkappaB-dependent cytokine production.J. Biol. Chem. 2005; 280: 38445-38456Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). were as previously with R. L. Mandrup S. receptor and activation of Cell. Biol. 2006; PubMed Scopus Google Scholar). cells were and differentiated in and with CLA, or TMB-8. cells were in and inhibitor and was by at were to and for with NFκB and in a of were in in to a of and for with were to the and were as previously and was by and were potential and C release were as of potential stress caused by 10,12 CLA and were as for the potential and for C was to the potential to the was to the cultures the of a were with and the was in a the of C in the cultures were of treatment and to to the from the as previously S. Brown J.M. Provo J.N. Hopkins R. McIntosh M.K. Conjugated linoleic acid promotes human adipocyte insulin resistance through NFkappaB-dependent cytokine production.J. Biol. Chem. 2005; 280: 38445-38456Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). C levels were by was from the cultures from to was was in an for possible in or the of the gene was for and these data from to was to and of to to of levels were to a by for was from cultures and in at differentiated cultures of human adipocytes were in with or of human were with 10,12 CLA, or 10,12 CLA KN-62 for insulin-stimulated uptake of was a with human insulin as previously (5.Brown J.M. Boysen M.S. Chung S. Fabiyi O. Morrison R.F. Mandrup S. McIntosh M.K. Conjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines.J. Biol. Chem. 2004; 279: 26735-26747Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). was to data was to of are as were the of CLA isomers on [Ca2+]i levels, we the a inhibitor that calcium O. a tumor intracellular Ca2+ by of the endoplasmic reticulum Sci. PubMed Scopus Google Scholar), was as a intracellular calcium levels in a Consistent with 10,12 CLA [Ca2+]i in a In 9,11 CLA [Ca2+]i levels to the was to the to which 10,12 CLA calcium from the ER. shown in attenuated the increase in [Ca2+]i mediated by and 10,12 CLA, that 10,12 CLA also calcium release from the ER. of adipocytes with the [Ca2+]i increase in [Ca2+]i attenuated the but not the effects of 10,12 CLA on [Ca2+]i In attenuated the but not the 10,12 CLA–mediated increase of that extracellular calcium a role in the regulation of [Ca2+]i by 10,12 CLA to the to which CLA causes calcium release from the cultures were with by a second treatment with or 10,12 CLA, and from increasing that calcium in human adipocytes attenuated 10,12 CLA from increasing [Ca2+]i In 10,12 CLA attenuated the effects of 10,12 CLA and on In CLA the increase in [Ca2+]i levels by 10,12 CLA, in cells with these data suggest that 10,12 CLA increases [Ca2+]i but not from the ER. the to which production of ROS and activation of and NFκB were dependent on we the effects of calcium and on and NFκB in ROS production was by 10,12 CLA in an isomer-specific 9,11 CLA data not which was by BAPTA, TMB-8, and KN-62, a CaMKII inhibitor. of ERK1/2 by was attenuated by that calcium release from the increases ERK1/2 activation. 10,12 CLA the of ERK1/2 in an isomer-specific which was attenuated by BAPTA, TMB-8, and KN-62 Consistent with these data, 10,12 CLA activation of JNK was also attenuated by BAPTA, TMB-8, and KN-62 KN-62 and attenuated 10,12 increase of protein These data suggest that and are of 10,12 CLA–mediated [Ca2+]i signaling and calcium-dependent the role of calcium in 10,12 CLA activation of cultures of human adipocytes were with for and over with 10,12 cells were of the of cells to the NFκB binding to inflammatory was treatment with 10,12 CLA NFκB binding to the IL-8 and which was by These data suggest that 10,12 CLA induction of NFκB binding to inflammatory is in by calcium release from the ER. on KN-62 CLA induction of ROS and the of 10,12 CLA on CaMKII mRNA levels was We that 10,12 CLA treatment for induced CaMKII β mRNA by which was attenuated by TMB-8. However, 10,12 CLA not increase the mRNA levels of the of CaMKII and data not integrated stress response has been shown to a role in 10,12 CLA induction of inflammation M. J. cis-12 conjugated linoleic acid the integrated stress response in 2007; PubMed Scopus Google Scholar). the of CLA on and inflammatory gene expression, cultures were with 9,11 CLA or 10,12 CLA for or Our that and 10,12 CLA not the expression of and inflammatory IL-8, by in an isomer-specific metabolic stress calcium release from we of and C However, C were by 10,12 CLA that 10,12 CLA not potential or we the of calcium release from the to induced IL-8 and gene expression, which was attenuated by we the role of [Ca2+]i in CLA induction of and inflammatory by cultures with or TMB-8, and with 10,12 CLA for 10,12 CLA induction of IL-8, and In gene expression by gene expression by Treatment with suppressed the 10,12 CLA-induced expression of IL-8, and reducing mRNA the role of CaMKII in 10,12 CLA induction of and inflammatory genes, cultures were with KN-62 attenuated or induction of IL-8, and gene expression These data suggest that 10,12 CLA induction of and inflammatory is to CaMKII activation and calcium release from the ER. However, of CaMKII is to this We the role of phospholipase C a protein involved in the release of calcium from intracellular Ca2+ by a lipid factor from Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), the inhibitor D609 attenuated 10,12 CLA increase of [Ca2+]i ROS and and inflammatory gene expression These data suggest that a role in 10,12 CLA of increase of and and inflammatory gene has been shown to suppress D.A. J.M. of of preadipocyte differentiation by prostaglandin PubMed Scopus Google Scholar) and is associated with inflammation and insulin resistance in humans CLA (10.Basu S. Riserus U. Turpeinen A. Vessby B. Conjugated linoleic acid induces lipid peroxidation in men with abdominal obesity.Clin. Sci. 2000; 99: 511-516Crossref PubMed Scopus (98) Google Scholar, 11.Riserus U. Basu S. Jovinge S. Fredrikson G.N. Arnlov J. Vessby B. Supplementation with conjugated linoleic acid causes isomer-dependent oxidative stress and elevated C-reactive protein: a potential link to fatty acid-induced insulin resistance.Circulation. 2002; 106: 1925-1929Crossref PubMed Scopus (267) Google Scholar, 12.Riserus U. Arner P. Brismar K. Vessby B. Treatment with dietary trans10cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome.Diabetes Care. 2002; 25: 1516-1521Crossref PubMed Scopus (368) Google Scholar). Consistent with these 10,12 CLA gene expression which was by BAPTA, TMB-8, and these we the role of [Ca2+]i in 10,12 CLA induction of the inflammatory Activation of of 10,12 CLA treatment and was isomer-specific However, suppressed 10,12 CLA–mediated of levels of of treatment KN-62 a these data that 10,12 CLA treatment increases inflammatory production in human adipocytes in vitro as in humans in and that this to of [Ca2+]i levels or CaMKII KN-62 10,12 CLA suppression of protein levels of treatment KN-62 10,12 CLA induction of gene expression and of insulin-stimulated glucose uptake of treatment but not These data that treatment with 10,12 CLA causes insulin resistance in human adipocytes that to on CaMKII activation but not on calcium release from the ER. of this was to the role of [Ca2+]i in 10,12 ROS inflammatory mRNA and protein levels, and insulin resistance in human these data for shown in that 10,12 on calcium signaling and markers of inflammation and insulin resistance in response initial response to CLA with an and release of calcium from the and the extracellular which to ROS and NFκB and and inflammatory gene second and response with activation and which to of causes of calcium signaling that to the suppression of and the of insulin Consistent with this second of calcium signaling has been reported to increase [Ca2+]i levels and activate CaMKII in murine adipocytes, to adipocyte differentiation D.A. J.M. of of preadipocyte differentiation by prostaglandin PubMed Scopus Google Scholar). In of calcium and ROS have been in the activation of NFκB and inflammation Activation of by stress Ca2+ and reactive oxygen as 129-136Crossref PubMed Scopus Google Scholar). we that calcium signaling with BAPTA, or KN-62 CLA–mediated ROS production that [Ca2+]i levels ROS production in human these attenuated 10,12 CLA–mediated activation of and NFκB and the expression of and inflammatory Consistent with these data, the inhibitor D609 attenuated 10,12 CLA increase in [Ca2+]i levels, and inflammatory gene expression these data the role of [Ca2+]i in ROS and inflammatory to 10,12 CLA in cultures of human of CLA–mediated insulin resistance by KN-62, but not TMB-8, that 10,12 CLA [Ca2+]i levels from the ER. KN-62 was as a inhibitor, this inhibitor has also been reported to T. M. A. M. KN-62, a inhibitor of protein kinase Biol. Chem. Full Text PDF PubMed Google Scholar, K. 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S. kinase II is for factor 2005; PubMed Scopus Google Scholar). these data that activation of ERK1/2 and JNK are to [Ca2+]i and We data that the CaMKII inhibitor KN-62 prevents 10,12 CLA–mediated insulin resistance Elevated [Ca2+]i levels have been to insulin resistance in cells B. K. M. D. of an of calcium for insulin-stimulated glucose in Biol. Chem. Full Text PDF PubMed Google Scholar, B. M. T. role of calcium in insulin resistance of and Clin. Invest. PubMed Scopus Google Scholar, B. and its of of insulin-stimulated glucose Biol. Chem. Full Text PDF PubMed Google Scholar), adipocytes B. D. M. D. K. of insulin resistance induced by levels of calcium in PubMed Scopus Google Scholar). In was shown to insulin resistance in a H.J. Kim Park of insulin by of intracellular in 2002; Full Text PDF PubMed Scopus Google Scholar). we not for glucose uptake studies due to its we were to that CLA or CaMKII protein levels not 10,12 CLA CaMKII β mRNA by we not increases CaMKII β protein or studies CaMKII β and gene are to the role of signaling on inflammation and insulin in cultures of human of murine adipocytes by 10,12 CLA in and in vitro has been to the M. J. cis-12 conjugated linoleic acid the integrated stress response in 2007; PubMed Scopus Google Scholar). These demonstrated that 10,12 CLA, but not 9,11 CLA, induced markers of the in and 3T3-L1 also suggest that the the induction of inflammatory gene expression and to delipidation by 10,12 Our data in cultures of human adipocytes are to these data in murine In 10,12 CLA has been shown to stress in a murine L. induced by linoleic acid is mediated by an endoplasmic reticulum stress Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). the and increase in [Ca2+]i levels by 10,12 CLA to increase ROS production and activate and stress response which in to activation of CaMKII and insulin resistance in cultures of human However, the by which 10,12 CLA increases and its on CaMKII activating factor acid body conjugated linoleic acid protein cyclooxygenase acid endoplasmic reticulum extracellular signal-related kinase and protein glucose interleukin integrated stress response kinase mitogen-activated protein kinase mitogen-activated protein kinase kinase nuclear factor prostaglandin phospholipase phospholipase C peroxisome proliferator activated receptor reactive oxygen species acid receptor of cytokine synthesis binding protein triglyceride
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