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Grant Number: 2R01DK063070-05A1
PI Name: MCINTOSH, MICHAEL K.
Project Title: Antiobesity Mechanism of CLA Isomer in Human Adipocytes
Abstract: DESCRIPTION (provided by applicant): Project Summary. 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 isomer-specific mechanisms by which conjugated linoleic acid (CLA), fatty acid (FA)s found in beef, dairy foods, and dietary supplements that decrease adiposity in certain animals and humans, reduces the triglyceride (TG) content of human adipocytes. The central hypothesis for this proposal is that trans-10, cis-12 CLA activates lipid-borne signals that suppress peroxisome proliferator activated receptor (PPAR)-? activity, thereby reducing the uptake of glucose and FAs for TG synthesis. This hypothesis is based on our findings demonstrating that trans-10, cis-12 CLA, but not cis-9, trans-11 CLA, directly increases the ratio of saturated FAs to monounsaturated FAs, and activates proinflammatory signals that suppress PPAR? activity. These actions of CLA are dependent on mitogen-activated protein kinase / extracellular signal-regulated kinase kinase (MEK/ERK) and nuclear factor kappa B (NF?B) signaling. The rationale for this research is that once we understand how trans-10, cis-12 CLA reduces the TG content of human adipocytes and identify potential metabolic consequences, it's effective and safe use as a dietary supplement for controlling obesity can be evaluated effectively. To accomplish these objectives, the following specific aims will be examined in primary cultures of human (pre) adipocytes: Aim #1. Identify the mechanism by which CLA regulates PPAR? in adipocytes; Aim #2. Determine the role of NF?B and MEK/ERK signaling in preadipocytes and adipocytes in mediating CLA's suppression of PPAR?; and Aim #3. Determine how CLA or its metabolites impact on signals that induce delipidation. In Aim #1, we will examine CLA's effects on the transcription and stability of PPAR? target genes, PPAR? phosphorylation, ligand-induced activation of a PPRE reporter, and recruitment of PPAR?, co-activators, co-repressors, and basal transcription factors to endogenous PPAR? target genes. In Aim #2, we will investigate the impact of chemical inhibitors and siRNAs targeting NF?B and MEK/ERK on the induction of our candidate cytokines and PPAR? target genes and on glucose and FA uptake and metabolism. In Aim #3, we will examine CLA's isomer-specific effects on the synthesis of lipids and cell signals known to activate NFKB and/or MEK/ERK and cause delipidation. Relevance. The proposed studies are significant because they are expected to lead to an in-depth understanding of the mechanism of action of CLA isomers and to promote the development of novel and safe dietary strategies for weight loss. As a consequence, reductions in health problems and financial costs related to obesity would be expected.
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