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Grant Abstract

Grant Number: 1R15DK059289-01
PI Name: Michael McIntosh
Project Title: CLA Reduces Adipogenesis In Human Preadipocytes

Abstract: DESCRIPTION (Scanned from the Applicant's Description): Dietary lipids contribute significantly to excess energy intake, which leads to the development of obesity and related diseases. However, certain fats when consumed in moderation promote health. For example, animal and cell culture studies have demonstrated antitumorigenic, antiatherogenic, and hypocholesterolemic properties of a crude mixture of isomers of conjugated linoleic acid (CLA), an unsaturated fatty acid found in beef and dairy foods. Furthermore, mice and pigs fed low levels of a commercially prepared mixture of CLA isomers (e.g., approximately 40 percent cis-9, trans-11 and 40 percent trans-10, cis-12 CLA) had less body fat than the controls. These studies suggest that the inclusion of CLA in the diet of animals may help prevent or attenuate the development of obesity and related diseases. However, effects of CLA on human body fat are conflicting. We believe that part of this discrepancy may be due to the type and amount of CLA isomers used in these studies. In support of this idea, we have recently demonstrated that the trans-10, cis-12, but not the cis-9, trans-11, isomer of CLA decreased the TG content of differentiating cultures of murine 3T3-L1 and human preadipocytes. These data suggest stereospecificity of CLA isomers and a possible regulatory role in adipogenesis. However, the mechanism(s) by which CLA alters the differentiation of preadipocytes is unclear. Furthermore, whereas CLA clearly attenuates body fat in animals, potential antiobesity properties of CLA in humans are disputable and require further examination. We hypothesize that CLA suppresses adipogenesis by reducing cellular levels of arachidonic acid (AA), an unsaturated fatty acid whose metabolites activate peroxisome proliferator activated receptor gamma (PPAR-gamma) and preadipocyte differentiation. In order to test this hypothesis, support is requested from this NIH AREA grant to examine in primary cultures of human preadipocytes: 1) whether CLA attenuates TG content by either suppressing lipogenesis, enhancing lipolysis, or decreasing the activation of PPAR-gamma, a lipid-activated transcription factor that controls adipogenesis; and 2) if CLA competes with linoleic acid for incorporation into cellular AA, a precursor of prostanoids that regulate adipocyte differentiation. Data obtained from this research are expected to expand our knowledge of how specific isomers of CLA influence human adipose tissue mass and the development of obesity and lead to the submission of a future NIH R01 grant.

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