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Biochemical, Molecular, and Genetic Mechanisms

Trans-10, Cis-12 Conjugated Linoleic Acid Antagonizes Ligand-Dependent PPAR Activity in Primary Cultures of Human Adipocytes^1,2

³ Department of Nutrition, University of North Carolina, Greensboro, NC 27402-6170 and ⁴ Department of Pathology, Wake Forest University, School of Medicine, Winston Salem, NC 27157

^* To whom correspondence should be addressed. E-mail: mkmcinto{at}uncg.edu.

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 PPAR target gene expression. We hypothesized that CLA antagonizes the activity of PPAR 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 PPAR by 10,12 CLA was accompanied by an increase in PPAR and extracellular signal-related kinase (ERK)1/2 phosphorylation, followed by decreased PPAR protein levels. To investigate if 10,12 CLA-mediated delipidation was preventable with a PPAR 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 PPAR 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 PPAR target genes. However, the levels of PPAR 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 PPAR activity, possibly via PPAR phosphorylation by ERK.