Title

Human Milk Oligosaccharide LNnT as a Novel Anti-Obesity Agent

Date of Award

6-2018

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Srujana Rayalam, PhD

Second Advisor

Avadhesh C. Sharma, PharmD, PhD

Third Advisor

Valerie E Cadet, PhD

Fourth Advisor

Richard White, PhD, FAHA

Abstract

Obesity is a chronic disease that is considered one of the greatest public epidemics with more than 2 billion adults worldwide classified as overweight or obese. This disease can be defined as an excess accumulation of white adipose tissue (WAT). This accumulation can lead to an increased risk of other chronic diseases such as cardiovascular disease, type 2 diabetes, and malignant disorders. While several therapeutic options attempting to reverse or reduce the effects of obesity are available, safe, effective, long-term treatments are limited. Another classic type of adipose tissue is brown adipose tissue (BAT). Unlike WAT which functions in energy storage, BAT functions to dissipate energy in the form of heat. This process is known as thermogenesis. Thermogenesis is the key mechanism associated with energy expenditure. It has been shown that the thermogenic properties of BAT is predominately accomplished by a mitochondrial protein called UCPI. WAT provides no protective mechanism against obesity due to the lack of UCPJ. Obese individuals thus exhibit a deficiency in thermogenesis leading to excessive weight gain.

It was previously believed that BAT disappears after infancy, however it has been recently discovered that adults also contain some BAT deposits. In light of this finding, researchers have begun investigating a newly identified type of adipose tissue in an attempt to combat obesity. Studies have suggested that WAT can be transdifferentiated into a brown-like adipose tissue called beige adipose tissue (BeAT) through a process known as browning/beiging. The activation of beige adipose tissue through sympathetic nervous system stimulation can lead to similar effects demonstrated by BAT. The immune properties of macrophages have also been suggested to play a role in beiging and thermogenesis of WAT.

Current obesity treatments such as surgical procedures and anti-obesity medications have serious and undesirable side effects. Consequently, safer and more natural therapeutic options are being explored for anti-obesity therapy. Immunomodulatory glycans found on the surface of helminth parasites and in human breast milk are being investigated for their anti-inflammatory and immunosuppressive mechanisms. Lacto-N-Fuctopentaose III (LNFPIII) found on Schistosome parasites has been reported to increase insulin sensitivity, enhance WAT insulin signaling through IL- 10 secretion, and suppress hepatic lipogenesis. A similar milk oligosaccharide, LactoN- neotetraose (LNnT) found at concentrations of 0.2-0.3g/L in human breast milk, as well as on the surface of Schistosome parasites, has been found to demonstrate antiinflammatory effects. However, there are currently no published studies on the antiobesity effects of these compound. In this current study, we will explore the novel antiobesity effects of LNnT to propose a multi-faceted approach for prevention and treatment of obesity. We propose to investigate the direct and indirect effects of LNnT on the induction of beiging of white adipocytes. The in vitro culture models utilized in this study are murine adipocytes (3T3-Ll) and macrophage (RA W264.7) cell lines. Western Blotting, ELISA, MitoTracker Green™, AdipoRed™ assay, Cayman Oxygen Consumption Rate assay, Glycerol assay, RT-PCR, Immunocytochemistry, Flow Cytometry, and a conditioned media culturing system were employed to demonstrate the effects of LNnT on beiging. Our data suggests that LNnT has the ability to directly induce transdifferentation of white to beige adipocytes and indirectly induce beiging by activating anti-inflammatory M2 macrophages.

This document is currently not available here.

Share

COinS