Investigating the mechanisms involved in the anti-obesity effect of conjugated linoleic acid (CLA) isomers in 3T3-L1 adipocytes, and in obese db/db and lean C57BL/6 mice

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Yeganeh, Azadeh
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The high rate of obesity is having a significant impact on human health. Understanding the underlying biological mechanisms that regulate adipogenesis and adipocyte lipid metabolism is necessary to identify novel approaches that promote weight loss. Conjugated linoleic acid (CLA) is an example of a naturally-derived product reported to exhibit an anti-obesity effect. For this thesis, it was hypothesized that the anti-obesity effects of the t10-c12 CLA isomer is due to lipid droplet dynamics alteration through activation of the Wnt/β-catenin pathway, which leads to weight loss via affecting adipogenesis and/or adipocyte death. Testing of this hypothesis was achieved by examining the effects of the most biologically active CLA isomers, cis-9, trans-11 (c9-t11), trans-10, cis-12 (t10-c12) CLA using in vitro (3T3-L1 cell line) and in vivo (mouse) models. In 3T3-L1 preadipocytes, both c9-t11 and t10-c12 CLA stimulated early stage differentiation, while t10-c12 CLA inhibited late differentiation as indicated by fewer lipid droplets, lower adipokine levels, and decreased levels of perilipin-1 and phospho-perilipin-1 compared to null. The t10-c12 CLA isomer decreased hormone-sensitive lipase (HSL) levels and inhibited lipolysis by activating protein kinase Cα (PKCα). As well, t10-c12-CLA inhibited adipocyte differentiation by stabilizing β-catenin, which sequesters peroxisome proliferator-activated receptor-γ in an inactive complex. Reduced body weight in both db/db and C57B/L6 mice fed t10-c12 CLA was due to less white and brown fat mass without changes in lean body mass or an alteration in feed intake compared to their respective control. t10-c12 CLA did not stimulate cell death in white adipose tissue. Immune cell infiltration was decreased in calorie restricted pair weight control mice, but not with CLA. t10-c12 CLA-induced weight loss did not improve hyperglycemia in db/db mice. In conclusion, the anti-adipogenic effects of t10-c12 CLA in vitro result from stabilization of β-catenin, which alters lipid droplet dynamics through HSL levels and perilipin-1 phosphorylation via the activation of PKCα. In contrast, t10-c12 CLA promotes loss of adipose tissue in vivo, possibly by activating β-catenin, but without influencing either adipogenesis or adipocyte clearance. This study suggests a novel mechanism for the anti-obesity effect of t10-c12 CLA, and highlights the possible side-effects associated with t10-c12 CLA consumption.
obesity, adipocytes, conjugated linoleic acid, Beta-catenin, Perilipin