Alterations in Adipocyte Lipid Metabolism by Trans-10, Cis-12 CLA Supplementation

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DESCRIPTION (provided by applicant): Conjugated linoleic acid (CLA) is a natural dietary trans fatty acid reported to promote weight loss by unknown mechanisms. One specific isoform of CLA, trans-10, cis-12 (t10,c12) CLA, is associated with reduced adiposity, which is beneficial, while simultaneously promoting systemic inflammation, insulin resistance, and dyslipidemia, all of which could be detrimental. These seemingly opposing effects of t10,c12-CLA have not yet been examined in the context of the metabolic syndrome, a common condition in which visceral obesity is associated with adipose tissue inflammation, dyslipidemia, and insulin resistance. Commercially available CLA supplements containing t10,c12-CLA are widely used to facilitate weight loss, so the opposing effects on body weight and inflammation could put consumers at risk of the potential for long-term adverse health effects. It is therefore important to better understand mechanisms by which t10,c12-CLA affects adipose tissue metabolism. Our preliminary studies have begun to investigate mechanisms by which t10,c12-CLA reduces adiposity. We have determined that mitochondrial metabolism is substantially increased in cultured adipocytes, with concomitant increases in inflammatory and monocyte chemotactic factor gene expression. Specifically, mitochondrial fatty acid oxidation is enhanced by t10,c12-CLA in white adipocytes, a process normally reserved for brown adipocytes, skeletal muscle, cardiac muscle, and hepatocytes. Our overall hypothesis is that t10,c12-CLA contributes to impaired lipid storage in adipose tissue by altering the lipid metabolism of white adipocytes towards a unique brown adipocyte-like phenotype at the expense of causing inflammatory changes in adipose tissue. In this application, we will further examine the effects of t10,c12-CLA on adipocyte lipid metabolism and inflammation as it relates to the metabolic state frequently associated with obesity. We will perform in vitro experiments to survey additional mechanisms related to enhanced fatty acid oxidation, such as altered glucose or fatty acid uptake, re-esterification of fatty acids, expression and function of lipid droplet-associated proteins, and lipolysis in adipocytes exposed to t10,c12-CLA. To assess t10,c12- CLA-induced changes in adipose tissue metabolism in vivo, we will supplement male Ldlr-/- mice with established obesity with one precent t10,c12-CLA, which mirrors human supplementation. Whole body weight, composition, energy expenditure, locomotion, thermogenic capacity, and insulin sensitivity will be assessed, and adipose tissue depots (epididymal, inguinal, mesenteric, retroperitoneal, and subscapular brown) will be examined for mass, morphology, macrophage accumulation, and fatty acid oxidative capacity. With further investigation into the biochemical pathways involved in adipocyte and metabolic responses to t10,c12-CLA, it might be possible to harness the anti-obesity potential of this novel dietary supplement, while eliminating its potentially adverse effects on inflammation and insulin resistance.