Piceatannol Involvement in Mechanisms of Cancer Cachexia, Obesity, and Other Metabolic Disorders
Energy metabolism encompasses fundamental processes that govern whole-body and cellular mechanisms. Consequently, it follows that aberrant metabolism results in unfavorable outcomes. This dissertation outlines mechanisms by which piceatannol, a dietary polyphenol, may ameliorate dysfunctional energy metabolism. Specifically, we explore the role of piceatannol in perturbations associated with cancer-associated cachexia (CAC) and diet-induced obesity (DIO). CAC is characterized by ongoing loss of lean muscle and adipose that cannot be overcome with nutritional interventions. DIO increases risk factors, such as insulin resistance, inflammation, hypertension, and dyslipidemia, for a number of chronic disease. In the etiology of both diseases, lipid metabolism plays a central role. In chapter 2, we modeled cancer-associated lipolysis using both cachexia-associated cytokines, TNF-α and interleukin-6, and cancer-conditioned media. We found that piceatannol blocked cancer-associated lipolysis in vitro . We further confirmed that piceatannol induced degradation of the key lipolytic enzyme, adipose triglyceride lipase. Mechanisms by which conditioned media induced lipolysis were also explored, in addition to a more in-depth analysis of piceatannol’s effect on exosome secretion, as described in supplemental material found in chapter 6. In vivo , we observed a strong protective trend of piceatannol against tumor-induced weight loss in mice. Body composition analysis revealed a similar trend in preservation of lean body mass. In chapter 3, we evaluated the role of piceatannol in DIO. Although we did not observe an effect of piceatannol on glucose tolerance or body weight in either a treatment or prevention model, a decrease in visceral white adipose tissue was observed in obese mice. Furthermore, we observed decreased expression of lipogenic genes, lower serum leptin, and lower respiratory exchange ratio in piceatannol-treated mice, all of which suggest adipose-reducing properties of piceatannol. Through proteomic analysis, we identified previously unknown piceatannol targets in 3T3-L1 adipocytes, as outlined in chapter 4. A total of 115 proteins were altered by piceatannol treatment, of which more than one third were associated with energy and metabolism cellular functions. Specifically, we identified several proteins involved in lipid and glucose metabolism that were affected by piceatannol treatment. In addition, we identified novel piceatannol targets, adipocyte plasma membrane-associated protein and AHNAK protein, which merit further investigation due to their involvement in obesity and insulin resistance. Overall, this dissertation proposes several mechanisms by which piceatannol modulates energy metabolism. Piceatannol inhibition of lipolysis, specifically, may be central to therapeutic effects in both CAC and obesity, as discussed in chapter 5. Future research investigating the role of piceatannol in preserving body weight and modulating glucose tolerance, especially in humans, is needed to translate these findings to recommendations for human disease.
Kim, Purdue University.
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