Degree Type

Dissertation

Date of Award

2011

Degree Name

Doctor of Philosophy

Department

Food Science and Human Nutrition

First Advisor

Michael E. Spurlock

Abstract

Obesity is characterized by decreased production of the anti-inflammatory hormone, adiponectin, increased secretion of pro-inflammatory cytokines and chemokines, and increased risk of colon cancer. Although adiponectin has been negatively associated with colorectal cancer development in human population, the role of adiponectin in colon tumorigenesis is unknown. The anti-inflammatory dietary polyphenol, resveratrol (RSV), increases circulating adiponectin concentrations in vivo, and has been shown to be effective in prevention of colorectal cancer and obesity-related morbidities. However, the effect of RSV supplementation on obesity-linked colorectal cancer had not been previously reported.

We first used an adiponectin knockout mouse model to investigate the role of adiponectin in obesity-associated colorectal cancer. In this study, we showed that in the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced mouse model of colorectal cancer, adiponectin genotype, high fat diet, and gender regulate colon carcinogenesis. Specifically, development of early lesions (aberrant crypt and mucin-depleted foci) was dependent on adiponectin genotype whereas the development of advanced lesions (intramucosal and invasive carcinomas) was dependent on diet and sex of the mice. Interestingly, adiponectin wildtype (Wt) mice had a greater number of total lesions than the knockout (KO) mice suggesting that under pro-inflammatory conditions, the presence of adiponectin promotes colonic tumorigenesis.

We next investigated the interaction between RSV and adiponectin in early colon tumorigenesis under obesigenic conditions. In this study, we showed that low-dose dietary RSV (20 mg/kg diet) had a tendency to decrease the number of aberrant crypt foci in Wt but not KO mice. Similarly, RSV had a tendency to reduce circulating pro-inflammatory cytokine and insulin concentrations, prevent adipocyte hypertrophy, and increase lean mass in Wt mice only. Taken together, RSV had a tendency to interact with adiponectin to attenuate tumorigenesis and the metabolic effects of obesity in vivo. We further investigated the interaction between adiponectin and RSV in vitro through the use of adipocytes derived from adiponectin KO and Wt mice and a colon cancer cell line. Here we showed that in adipocytes but not colon cancer cells, the anti-inflammatory effects of RSV are dependent on adiponectin.

Finally, we compared the effects of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) inhibitors in the attenuation of LPS-induced inflammation by RSV among human adipocyte, monocyte, and colon cancer cell lines. Results obtained from this series of cell culture experiments, suggests that RSV acted through different mechanisms to inhibit chronic LPS-induced inflammation among cell types. In adipocytes, RSV inhibited LPS-induced inflammation and lipolysis, and Sirt1 and AMPK inhibitors reversed this, respectively. In HT29 colon cancer cells, RSV inhibited ROS and proliferation, and the Sirt1 inhibitor, but not the AMPK inhibitor reversed this. Conversely, RSV's inhibition of LPS-induced inflammation in U937 monocytes was not reversed by Sirt1 or AMPK inhibitors. Thus, while Sirt1 appears to be important in the effects of RSV in adipocytes and colon cancer cells, we did not identify a role for Sirt1 or AMPK in RSV's anti-inflammatory action in monocytes.

Collectively, our data suggests that adiponectin, diet, and gender interact in the development of obesity-associated colon tumorigenesis under pro-inflammatory conditions. Moreover, we showed that RSV has a tendency to interact with adiponectin to attenuate tumorigenesis and improve the metabolic and inflammatory profile in obesity. These findings support the potential use of RSV as an anti-inflammatory dietary supplement aimed at prevention of obesity-associated colon tumorigenesis through anti-inflammatory function in adipose and colon tissues. Continued research is warranted to further elucidate the role of adiponectin and the cell- and tissue-specific actions of RSV in obesity-associated colon cancer.

Copyright Owner

Rebecca L. Boddicker

Language

en

Date Available

2012-04-06

File Format

application/pdf

File Size

149 pages

Included in

Nutrition Commons

Share

COinS