title: Diacylglycerol kinase inhibitor R59022 attenuates conjugated linoleic acid-mediated inflammation in human adipocytes.
abstract: Diacylglycerol kinases (DGK) convert diacylglycerol to phosphatidic acid, which has been reported to stimulate calcium release from the endoplasmic reticulum. Based on our published data showing that trans-10, cis-12 conjugated linoleic acid (t10,c12 CLA)-mediated intracellular calcium accumulation is linked to inflammation and insulin resistance, we hypothesized that inhibiting DGKs with R59022 would prevent t10,c12 CLA-mediated inflammatory signaling and insulin resistance in human adipocytes. Consistent with our hypothesis, R59022 attenuated t10,c12 CLA-mediated i) increased gene expression and protein secretion of interleukin (IL)-8, IL-6, and monocyte chemoattractant protein-1 (MCP-1); ii) increased activation of extracellular signal-related kinase (ERK), cJun-NH2-terminal kinase (JNK), and cJun; iii) increased intracellular calcium levels; iv) suppressed mRNA or protein levels of peroxisome proliferator activated receptor γ, adiponectin, and insulin-dependent glucose transporter 4; and v) decreased fatty acid and glucose uptake and triglyceride content. DGKη was targeted for investigation based on our findings that i) DGKη was highly expressed in primary human adipocytes and time-dependently induced by t10,c12 CLA and that ii) t10,c12 CLA-induced DGKη expression was dose-dependently decreased with R59022. Small interfering RNA (siRNA) targeting DGKη decreased t10,c12 CLA-induced DGKη, IL-8, and MCP-1 gene expression, as well as activation of JNK and cJun. Taken together, these data suggest that DGKs mediate, in part, t10,c12 CLA-induced inflammatory signaling in primary human adipocytes.
authors.affiliation: Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC.
authors.forename: Kristina
authors.initials: K
authors.lastname: Martinez
authors.affiliation: Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC.
authors.forename: Shruthi
authors.initials: S
authors.lastname: Shyamasundar
authors.affiliation: Department of Molecular Physiology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Arion
authors.initials: A
authors.lastname: Kennedy
authors.affiliation: Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC.
authors.forename: Chia Chi
authors.initials: CC
authors.lastname: Chuang
authors.affiliation: Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC.
authors.forename: Angel
authors.initials: A
authors.lastname: Marsh
authors.affiliation: Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kincaid
authors.affiliation: Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC.
authors.forename: Tanya
authors.initials: T
authors.lastname: Reid
authors.affiliation: Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC.
authors.forename: Michael
authors.initials: M
authors.lastname: McIntosh
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D016209:Interleukin-8; D044243:Linoleic Acids, Conjugated; D011744:Pyrimidinones; D013844:Thiazoles; C047505:R 59022; D019852:Diacylglycerol Kinase; D002118:Calcium