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Abstract
Dietary conjugated linoleic acid (CLA) reduces body fat in animals and some humans. Here we show that trans-10, cis-12 CLA, but not cis-9, trans-11 CLA, when added to cultures of stromal vascular cells containing newly differentiated human adipocytes, caused a time-dependent decrease in triglyceride content, insulin-stimulated glucose and fatty acid uptake, incorporation into lipid, and oxidation compared with controls. In parallel, gene expression of peroxisome proliferator-activated receptor-gamma and many of its downstream targets were diminished by trans-10, cis-12 CLA, whereas leptin gene expression was increased. Prior to changes in gene expression and metabolism, trans-10, cis-12 CLA caused a robust and sustained activation of mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) signaling. Furthermore, the trans-10, cis-12 CLA-mediated activation of MEK/ERK could be attenuated by pretreatment with U0126 and pertussis toxin. In parallel, pretreatment with U0126 blocked the ability of trans-10, cis-12 CLA to alter gene expression and attenuate glucose and fatty acid uptake of the cultures. Intriguingly, the induction by CLA of MEK/ERK signaling was linked to hypersecretion of adipocytokines interleukin-6 and interleukin-8. Collectively, these data demonstrate for the first time that trans-10, cis-12 CLA decreases the triglyceride content of newly differentiated human adipocytes by inducing MEK/ERK signaling through the autocrine/paracrine actions of interleukins-6 and 8.
Highlights
Dietary conjugated linoleic acid (CLA) reduces body fat in animals and some humans
Trans-10, Cis-12 CLA Attenuation of Glucose and fatty acid (FA) Uptake Is Reversed by U0126 and pertussis toxin (PTX)—To determine whether GPCRGi/o coupling and mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) signaling are obligate for the attenuation of glucose and lipid metabolism by CLA, we investigated the influence of PTX and U0126 on glucose and FA uptake in cultures of Stromal Vascular (SV) cells containing newly differentiated adipocytes. 2-[3H]Deoxyglucose (Fig. 8A) and [14C]oleic acid (Fig. 8B) uptake were lower in cultures treated with trans-10, cis-12 CLA for 24 h compared with controls
We demonstrate for the first time that trans-10, cis-12 CLA decreases the TG content of cultures of SV cells containing newly differentiated human adipocytes through MEK/ERK-dependent transcriptional control of genes involved in glucose and FA uptake and metabolism
Summary
We demonstrate that trans-10, cis-12 CLA activates ERK1/2, but not p38 or JNK MAPKs, protein-1; MIP-1␣, macrophage inflammatory protein-1␣; PBS, phosphate-buffered saline; PPAR-␥, peroxisome proliferator-activated receptor-␥; PTX, pertussis toxin; SV, stromal vascular; TBS, Tris-buffered saline; TG, triglyceride; TNF-␣, tumor necrosis factor-␣. Using protein array technology, we have identified IL-6 and IL-8 as critical autocrine/paracrine regulators of CLA-induced ERK activation These studies demonstrate for the first time that trans-10, cis-12 CLA induces the expression and secretion of the proinflammatory adipocytokines IL-6 and IL-8, and through autocrine and paracrine networks, these mediators reduce human adipocyte TG content by activating MEK/ ERK signaling
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