Trans-10, cis-12 conjugated linoleic acid antagonizes ligand-dependent PPARgamma activity in primary cultures of human adipocytes.
We previously demonstrated that trans-10, cis-12 (10,12) conjugated linoleic acid (CLA) causes human adipocyte delipidation, insulin resistance, and inflammation in part by attenuating PPARgamma target gene expression. We hypothesized that CLA antagonizes the activity of PPARgamma in an isomer-specific manner. 10,12 CLA, but not cis-9, trans-11 (9,11) CLA, suppressed ligand-stimulated activation of a peroxisome proliferator response element-luciferase reporter. This decreased activation of PPARgamma by 10,12 CLA was accompanied by an increase in PPARgamma and extracellular signal-related kinase (ERK)1/2 phosphorylation, followed by decreased PPARgamma protein levels. To investigate if 10,12 CLA-mediated delipidation was preventable with a PPARgamma ligand (BRL), cultures were treated for 1 wk with 10,12 CLA or 10,12 CLA + BRL and adipogenic gene and protein expression, glucose uptake, and triglyceride (TG) were measured. BRL cosupplementation completely prevented 10,12 CLA suppression of adipocyte fatty acid-binding protein, lipoprotein lipase, and perilipin mRNA levels without preventing reductions in PPARgamma or insulin-dependent glucose transporter 4 (GLUT4) expression, glucose uptake, or TG. Lastly, we investigated the impact of CLA withdrawal in the absence or presence of BRL for 2 wk. CLA withdrawal did not rescue CLA-mediated reductions in adipogenic gene and protein expression. In contrast, BRL supplementation for 2 wk following CLA withdrawal rescued mRNA levels of PPARgamma target genes. However, the levels of PPARgamma and GLUT4 protein and TG were only partially rescued by BRL. Collectively, we demonstrate for the first time, to our knowledge, that 10,12 CLA antagonizes ligand-dependent PPARgamma activity, possibly via PPARgamma phosphorylation by ERK.
Kennedy
Arion
A
Department of Nutrition, University of North Carolina, Greensboro, NC 27402-6170, USA.
Chung
Soonkyu
S
LaPoint
Kathleen
K
Fabiyi
Oluwatoyin
O
McIntosh
Michael K
MK
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004347:Drug Interactions; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008024:Ligands; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D008024:Ligands; D044243:Linoleic Acids, Conjugated; D047495:PPAR gamma; D045162:Thiazolidinediones; C496197:trans-10,cis-12-conjugated linoleic acid; D000077154:Rosiglitazone