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Masters Theses
Date of Award
12-2004
Degree Type
Thesis
Degree Name
Master of Science
Major
Nutrition
Major Professor
Naima Moustaid-Moussa
Committee Members
Jay Whelan, Betsy Haughton
Abstract
With the current focus on the role of n-3 PUFAs as beneficial dietary interventions in the fields of cardiovascular disease and cancer, there has been a vastly increased awareness and focus on the mechanism of action for these essential fatty acids.
Many of the effects of PUFAs are mediated via changes in prostaglandin (PG) levels. One primary substrate for PGs is arachidonic acid (AA) (20:4 n-6), which results in the production of 2-series PGs. Increased concentrations of AA have been shown to increase levels of PGE2 in vitro and in vivo. The omega-3 fatty acid EPA (20:5 n-3) is of particular interest due to its incorporation into cell membrane phospholipids in competition with AA. EPA can also serve as a substrate for prostaglandin production when present in tissue and results in the production of 3-series PGs, which do not appear to produce the same effects as 2-series PGs, although data is extremely limited. The secretion of prostaglandins (PGs), and specifically PGE2 has been demonstrated in human and rodent adipocytes, and the presence of PGE2 receptors in these tissues has also been demonstrated. PGE2 can act in an autocrine/paracrine fashion in adipocytes to decrease lipolysis via G-protein coupled receptors. Preliminary data from our lab on ApcMin/+ mice showed that cyclooxygenase (COX) inhibition significantly reduced the activity of fatty acid synthase (FAS) in adipose tissue, and PGE2 receptor agonists partially but significantly reversed this effect.
Our overall objective was to determine whether treatment with EPA or selective COX-2 inhibitors would lead to a reduction in measured PGE2 that would in turn regulate markers of lipogenesis. We hypothesized that increased levels of EPA would competitively reduce tissue AA levels, and consequently PGE2 production, leading to decreased activity of markers specific to adipogenesis, specifically the FAS enzyme. Selective COX-2 inhibition was expected to produce similar effects via inhibition of COX metabolism of AA to PGs. Studies were conducted on 3T3-L1 adipocytes. Dose-response studies demonstrated a clear relationship between increasing doses of EPA or AA and measured PGE2/PGE3 levels. Manipulation of PGE2 levels via addition of EPA to culture media led to significant changes in measured PGE2 levels versus AA, but did not result in a significant decrease in FAS enzyme activity. Addition of celecoxib, a selective COX-2 inhibitor (CI), to culture media resulted in a significant decrease in PGE2levels and FAS activity. Addition of exogenous PGE2 to CI treatment did not reverse the decreased FAS enzyme activity. These results indicate that addition of EPA can displace AA in cell membrane phospholipids and reduce PGE2 production, but does not impact FAS activity. Suppression of PGE2 by selective COX-2 inhibition does lead to decreased FAS activity, which is not reversed by exogenous PGE2 addition.
Recommended Citation
Wortman, Patrick Allen, "Prostaglandin E2 Secretion and Effect on Adipocyte Lipogenesis. " Master's Thesis, University of Tennessee, 2004.
https://trace.tennessee.edu/utk_gradthes/4825