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Grant Abstract

Grant Number: 5R01DK063070-03
PI Name: Michael McIntosh
Project Title: Antiobesity Mechanism of CLA Isomer in Human Adipocytes

Abstract: DESCRIPTION (provided by applicant): The long-term goal of this project is to develop novel dietary strategies for the control of human obesity, the most prevalent nutrition-related disease in America. The objective of this application is to identify isomerspecific mechanisms by which conjugated linoleic acid (CLA), unsaturated fatty acids found in beef and dairy foods that reduce adiposity in certain animals and humans, alters lipid metabolism in cultures of human (pre)adipocytes. The central hypothesis for the proposed research is that the trans-10, cis-12 isomer of CLA attenuates triglyceride (TG) content and alters lipid droplet morphology by enhancing energy expenditure, lipolysis, and fatty acid oxidation, thereby down-regulating the expression of perilipin-A, a major regulator of adipocyte TG storage. This hypothesis was formulated based on our preliminary findings in human (pre)adipocyte cultures demonstrating that trans-10, cis-12, but not cis-9, trans-11, CLA decreased TG content, de novo lipogenesis, fatty acid esterification, and perilipin protein without affecting differentiation per se. The rationale for the proposed research is that once we understand how trans-10, cis-12 CLA prevents TG accumulation in (pre)adipocytes, effective strategies can be developed using CLA as an antiobesity nutrient in fortified foods or supplements for clinical trials. To accomplish this objective, the following specific aims will be examined in human cultures of differentiating preadipocytes and newly differentiated adipocytes: Aim #1. Determine the mechanism by which trans-10, cis-12 CLA decreases cellular TG content; and Aim #2. Determine the mechanism by which trans-10, cis-12 CLA decreases the expression of perilipin-A. In Aim #1, the impact of fatty acid type and dose on oxygen consumption, mitochondrial and peroxisomal beta-oxidation, lipolysis, fatty acid oxidation, and uncoupling protein expression will be determined. In Aim #2, the influence of fatty acid type and dose on perilipin-A protein and gene expression will be evaluated. Using primary cultures of human adipocytes as our model is important, because there are clear differences between the lipid metabolism of human and animal adipocytes. The proposed studies are significant because they are expected to lead to the development of novel strategies for weight loss. Consequently, reductions in health problems and financial costs related to obesity are expected.

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