Date of Award

8-2017

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Adwoa Aduonum

Second Advisor

Jack Chapman

Third Advisor

Karla Thomason

Fourth Advisor

Shafik Habal

Abstract

Obesity, a chronic disease, is a global epidemic that affects millions of lives and increases the risk of several comorbidities such as Type 2 diabetes, musculoskeletal disorders, cardiovascular disease, and cancer. Obesity is the leading cause of death globally, and is associated with an excessive accumulation of white adipose tissue (WAT). Although obesity is a serious condition, safe, long-term drug therapies are limited. A second type of adipose tissue is known as brown adipose tissue (BAT), which functions as an energy dissipater in the form of heat, as opposed to energy storing WAT. Previous research has shown that the mitochondrial uncoupling protein 1 (UCP1), activates the thermogenic properties of BAT [1]. WAT lacks the expression of UCP1 and therefore has no protective mechanisms against obesity and stores energy in the form of triglycerides. Thermogenic BAT has been identified in adult humans [2], as such, this discovery has been an attractive target for anti-obesity therapy. Recently, studies have suggested that WAT can be transdifferentiated into brown-like beige adipose tissue (BeAT). This transdifferentiation process is referred to as “beiging” and is mediated by the activation of the sympathetic nervous system. Activation of BeAT, similar to BAT, generates heat at the expense of ATP. Additionally, immune cells like macrophages play an important role in the induction of thermogenesis in WAT and contribute to the beiging of WAT [3]. Samuels v Current treatments for obesity, as well as “browning” agents, propose their own risks to humans and are not ideal long-term solutions for anti-obesity therapy. Consequently, many phytochemicals have been explored for their safe anti-obesity affects and as browning agents. Recently, xanthohumol (XN), a prenylated flavonoid found in Hops flowers, has been reported to inhibit adipogenesis and stimulate the apoptosis of adipocytes [4]. However, there are no published studies demonstrating the effects of XN on thermogenesis. In this current study, we will explore novel anti-obesity effects of XN to propose a multi-faceted approach for prevention and treatment of obesity. We propose to investigate the direct and indirect effects of XN on the induction of beiging in white adipocytes. Furthermore, we will investigate the role of adenosine monophosphate activated kinase (AMPK) signaling pathway in the induction of beiging. The in vitro cell culture models utilized in this study are murine adipocyte (3T3-L1) and macrophage (RAW264.7) cell lines. Cell viability assay, Western blotting, ELISA, MitoTracker Green™, Oil Red O staining, AdipoRed™ assay, and a Transwell co-culturing system are employed to demonstrate the effects of XN on beiging and the role of AMPK pathway in XN-induced beiging. Our data suggests that XN has the ability to directly induce transdifferentiation of white to beige adipocytes and indirectly induce beiging by activating anti-inflammatory M2 macrophages. Furthermore, data also indicates a role of the AMPK pathway in XN-mediated anti-obesity effects.

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