Obesity, which is the leading causes of increased mortality and morbidity in the U.S., is now a global health problem. Adipogenesis, elevated inflammatory response, and high level of endoplasmic reticulum (ER) stress in adipocytes have been known to contribute to the development of obesity and its complications. Furthermore, recent studies suggest that intestinal barrier function plays an important role in obesity-induced inflammation. Despite having continuous attention on dietary phytochemicals as therapeutic and/or preventive agents against many diseases, a few such compounds are known to have an anti-obese property. The goals of this study are to identify dietary bioactive components which counteract obesity through modulating adipocyte development and intestinal functions. To achieve our goals, curcumin (CCM) and selenium have been selected and tested in an in vitro cell culture model. First, our study reveals that CCM suppresses adipocyte differentiation through inhibition of mitotic clonal expansion. Chapter 2 addresses the molecular mechanisms of how CCM inhibits adipogenesis in vitro. Even though CCM is believed to be a potent anti-obesity agent, poor bioavailability due to lack of water-solubility limits its usage. Thus, water-soluble CCM has been developed by conjugating with polyethylene glycol (CCM-PEG). Chapter 3 investigates cellular retention and potential anti-obesity function of water-soluble CCM-conjugated with polyethylene glycol (CCM-PEG). We elucidated that CCM-PEG had improved cellular retention and its anti-adipogenic property in preadipocytes. Besides its health benefit in body weight management, CCM is suggested to enhance intestinal function. Obesity results in altered intestinal tight junction barrier function, contributing systemic inflammation. In addition, multifunctional leptin is postitively correlated with obesity and gastric leptin affects intestinal function including inflammation and nutrient uptake. However, the direct role of leptin on intestinal barrier function remains to be elucidated. We hypothesized that leptin deteriorates intestinal tight junction function. Chapter 4 elucidated that gastric leptin alters intestinal barrier function via suppression of tight junction-related protein expression in human intestine Caco-2 BBe cells with increased levels of genes encoding pro-inflammatory cytokines. These adverse actions of leptin, however, were abolished by CCM pretreatment. These results suggest the possibility that leptin could be a link between obesity and obesity-induced inflammation. Moreover, dietary component CCM could be able to uncouple the link between obesity and leptin-induced intestinal dysfunction. Second, anti-adipogenic function of selenium, an essential micronutrient, has been demonstrated in vivo cell culture system in chapter 7. Selenium is known to have anti-cancer, anti-oxidative properties, but its role in obesity is unknown. Since ER stress is critical for adipogenesis program and selenium acts through incorporation into selenoproteins, we hypothesize that selenium prevents adipogenesis through attenuation of ER stress and induction of selenoprotein. An inorganic selenium selenate, but not other forms of selenium, exhibited an anti-adipogenic activity through attenuation of ER stress. In chapter 6, we identified that ER resident selenoprotein SEPS1 has a pivotal role in adipogenesis. Dexamethasone in adipogenic cocktail induced SEPS1 protein degradation during the early stage of differentiation, thus helping to procede adipogenesis. Selenate elevated SEPS1 expression in preadipocytes and protected SEPS1 degradation. Although more studies are needed to elucidate the requirement of SEPS1 for selenate\u27s anti-adipogenic function, our results indicate that inorganic selenium, selenate, exhibited an anti-adipogenesis activity possibly through attenuation of ER stress and/or induction of SEPS1. Taken together, our studies provide evidence that bioactive dietary components like CCM and selenate block the expansion of adipose tissue mass. Moreover, our results suggest the possibility that CCM may prevent obesity-increased systemic inflammation through enhancing intestinal barrier function. Overall, our findings provide scientific evidence of new dietary strategies for an effective prevention of obesity and obesity-related health complications
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