Title

The Multifaceted Effects of Guggulsterone as an Anti-Obesity Agent

Date of Award

7-2016

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Srujana Rayalam, PhD

Second Advisor

Harold Komiskey, PhD

Third Advisor

Rangaiah Shashidharamurthy, PhD

Fourth Advisor

Xinyu (Eric) Wang, PhD

Fifth Advisor

Richard E. White, PhD

Abstract

Obesity is associated with pathological expansion of white adipose tissue (WAT) and is the leading cause of morbidity and mortality worldwide. In this study, we explored the multifaceted effects of guggulsterone (GS), a well-studied phytosterol for its cholesterol lowering effects, as an anti-obesity agent. We investigated the effects of GS on adipogenesis, lipolysis and beiging using 3T3-L1 murine adipocyte cell line. Identification of clusters of brown adipocyte-like cells in white adipose tissue depots indicate a mechanism by which WAT acquires brown adipose tissue (BAT)-like properties, generally referred to as 'beiging'. Beiging of WAT increases energy expenditure and is gaining attention as a novel therapeutic approach for obesity. We demonstrate the three-way antiobesity effects of GS in in-vitro cell culture model. Firstly, GS inhibited the differentiation of preadipocytes to mature adipocytes contributing to the overall decrease in adipogenesis. Secondly, GS promoted lipolysis in mature adipocytes as evidenced by the increase in free glycerol release with GS treatment. Finally, we have demonstrated the effects of GS on upregulating beige specific markers in mature adipocytes like uncoupling protein 1 (UCP1) and T-box transcription factor 1 (Tbx1) and thermogenic markers like peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and peroxisome proliferator-activated receptor gamma (PPARγ). Additionally, GS also increased mitochondrial biogenesis, another indicator for the induction of beiging. GS is structurally similar to bile acids and we hypothesize that GS-induced effects on adipocytes are mediated through, TGR5, a bile acid receptor. Our results indicate that GS increases TGR5 and type 2 deiodinase (DIO2), a downstream marker of TGR5 activation, expression in mature adipocytes. We also used a TGR5 agonist INT-777 and observed GS in combination with INT-777 increases the expression of UCP1. Together, this data suggests that guggulsterone may exert anti-obesity effects not only by decreasing adipogenesis and promoting lipolysis in WAT, but also by inducing white to beige transdifferentiation thereby increasing thermogenesis and promoting weight loss.

This document is currently not available here.

Share

COinS