title: JNK inhibition by SP600125 attenuates trans-10, cis-12 conjugated linoleic acid-mediated regulation of inflammatory and lipogenic gene expression.
abstract: Supplementation with a mixture of trans-10, cis-12 (t10,c12) and cis-9, trans-11 (c9,t11) isomers of conjugated linoleic acid (CLA), or t10,c12 CLA alone, reduces body weight and fat deposition in animals and some humans. However, these anti-obesity actions of t10,c12 CLA are routinely accompanied by increased markers of inflammation and insulin resistance. Thus, we examined the extent to which blocking c-Jun NH2-terminal kinase (JNK) signaling using the JNK inhibitor SP600125 attenuated markers of inflammation and insulin resistance in primary human adipocytes treated with t10,c12 CLA. SP600125 attenuated t10,c12 CLA-mediated phosphorylation of cJun and increased protein levels of activating transcription factor (ATF) 3, two downstream targets of JNK. SP600125 attenuated t10,c12 CLA-mediated induction of inflammatory genes, including interleukin (IL)-6, IL-8, IL-1β, ATF3, monocyte chemoattractant protein (MCP)-1, and cyclooxygenase-2. Consistent with these data, SP600125 prevented t10,c12 CLA-mediated secretion of IL-8, IL-6, and MCP-1. SP600125 prevented t10,c12 CLA suppression of lipogenic genes including peroxisome proliferator activated receptor gamma, liver X receptor, sterol regulatory element binding protein, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. Additionally, SP600125 blocked t10,c12 CLA-mediated induction of suppressor of cytokine synthesis-3 and suppression of adiponectin and insulin-dependent glucose transporter 4 mRNA levels. Collectively, these data suggest that JNK signaling plays an important role in t10,c12 CLA-mediated regulation of inflammatory and lipogenic gene expression in primary cultures of human adipocytes.
authors: Department of Nutrition, University of North Carolina, 318 Stone Building, PO Box 26170, Greensboro, NC 27402-6170, USA. kbmarti2@uncg.edu
authors: Kristina
authors: K
authors: Martinez
authors: Arion
authors: A
authors: Kennedy
authors: Michael K
authors: MK
authors: McIntosh
mesh_terms: D051700:Activating Transcription Factor 3 / Q000276:immunology; D017667:Adipocytes / Q000187:drug effects* / Q000276:immunology; D000328:Adult; D000873:Anthracenes / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D044243:Linoleic Acids, Conjugated / Q000276:immunology*; D050155:Lipogenesis / Q000187:drug effects; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000873:Anthracenes; D044243:Linoleic Acids, Conjugated; C496197:trans-10,cis-12-conjugated linoleic acid; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases