| Given the steady rise in obesity worldwide, it is important to identify dietary compounds that prevent adiposity. One dietary strategy is supplementation with conjugated linoleic acid (CLA), which has been demonstrated to reduce body fat mass. However, side effects associated with CLA supplementation include inflammation, insulin resistance, and dyslipidemia. Elucidation of the antiobesity mechanism of CLA is critical for evaluating its efficacy and safety as a dietary supplement for treating obesity. Therefore, this research examined the upstream mechanism by which CLA induced inflammation, insulin resistance, and delipidation of human adipocytes.;Our research group has previously demonstrated that trans-10, cis-12 (10,12) CLA causes delipidation of human adipocytes via activating nuclear factor kappa B (NFkappaB) and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK/ERK) signaling, leading to inflammation and the suppression of peroxisome proliferator activated receptor (PPARgamma) and decreased glucose and fatty acid uptake. Based on these findings, the following questions were addressed using primary cultures of newly differentiated human adipocytes as a cell model (1) How does CLA impact PPARgamma activity?, (2) What upstream mechanisms activate ERK, NFkappaB and induce inflammation?, and (3) Does resveratrol, a phenolic phytochemical with antioxidant properties, attenuate CLA-induced inflammation, insulin resistance, and delipidation?;Answers to these questions were as follows. (1) 10,12 CLA antagonized ligand-dependent PPARgamma activity, possibly via PPARgamma phosphorylation by ERK. 10,12 CLA suppression of PPARgamma and insulin-stimulated glucose uptake, along with delipidation were partially rescued by co-supplementation with the PPARgamma agonist BRL, further supporting CLA antagonizing PPARgamma. (2) Cultures treated with TMB-8, an inhibitor of calcium release from the endoplasmic reticulum or KN-62, an inhibitor of calcium/calmodulin-dependent kinase II (CAMKII) attenuated 10,12 CLA-mediated reactive oxygen species (ROS) production, mitogen-activated protein kinase (MAPK) activation, inflammatory gene induction, and insulin resistance. These data suggested that 10,12 CLA-mediated inflammation and insulin resistance are dependent on calcium release from the endoplasmic reticulum or CAMKII. (3) Treatment with resveratrol prevented 10,12 CLA-mediated inflammation and insulin resistance by attenuating intracellular calcium, ROS, and inflammation, by increasing PPARgamma activity. Collectively, these data suggest that one of the antiobesity mechanisms of 10,12 CLA is inducing cellular stress and inflammation which antagonize PPARgamma, leading to insulin resistance and delipidation of human adipocytes. |
