News & Research

    University of Texas Southwestern Medical Center, Dallas, Texas

Modulation of adiposity by 27-hydroxycholesterol, the first identified endogenous SERM

General Research Subject: Obesity

Focus: Adipocytes, Obesity\Animal Models

Type of Grant: Junior Faculty

Project Start Date: July 1, 2011

Project End Date: June 30, 2014

Research Description

During the development of obesity and atherosclerosis, or hardening of the arteries, compounds known as oxysterols derived from cholesterol, as well as cholesterol itself, accumulate in the blood vessel wall. Recently, we found in blood vessel cells grown in culture that certain oxysterols inhibit the beneficial effects of the hormone estrogen, which occur by the activation of proteins called estrogen receptors (ER). In addition, the mice with high level of one of these oxysterols known as 27-hydroxycholesterol have more body fat and less bone density compared to normal mice. Our goal in the present research is to understand the physiological effects of oxysterols on ERs in the population changes between the cells that develop to store fat and the cells that develop to make bones. Furthermore, the possibility that obesity that comes from excess calory diet is suppressed by inhibiting blood 27-hydroxycholesterol levels, even when the blood cholesterol levels remain high, will be tested. Experiments will be performed in normal mice, and also in the mice with elevated or decreased levels of 27-hydroxycholesterol. Upon completion of this project we hope to further our understanding of the precise mechanisms that compromise the beneficial effects of estrogen replacement therapy on the cardiovascular system. Ultimately, this project has the potential to establish novel therapeutic approaches toward obesity, atherosclerosis, and other blood vessel diseases.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

Obesity accounts for most of the risk of cardiovascular disease worldwide in both men and women and at all ages. Obesity increases dramatically the probability of developing type 2 diabetes, dyslipidemia, and cardiovascular disease.  During the development of obesity and atherosclerosis, or hardening of the arteries, compounds known as oxysterols derived from cholesterol, as well as cholesterol itself, accumulate in the blood vessel wall.  Recently we found in blood vessel cells grown in culture that certain oxysterols inhibit the beneficial effects of the hormone estrogen.  In addition the mice with high level of these oxysterols have more body fat and less bone density compared to normal mice.  My research project is to understand the physiological effects of oxysterols in the population changes between the cells that develop to storage fat and the cells that make bones.  Furthermore, the possibility that obesity that comes from excess calorie diet is suppressed by inhibiting blood oxysterol levels, even when the blood cholesterol level remains high, will be tested.  Upon completion of this project we hope to further our understanding of the precise mechanisms that compromise the beneficial effects of estrogen replacement therapy on obesity.  Ultimately, this project has the potential to establish novel therapeutic approaches toward obesity, which is closely related to the development of diabetes.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Since this project is a basic science with the use of mouse models, this project does not directly link to the establishment of treatments on diabetes in human.  However, my project is to examine a novel mechanism that is important from our current results so far for the development of obesity and diabetes but has not been investigated at all by others.  Furthermore, we will test the possibility that obesity that comes from excess calorie diet is suppressed by inhibiting blood oxysterol levels, even when the blood cholesterol level remains high.  Therefore, my project has a potential to develop a completely new concept toward the mechanisms of obesity, which is closely related to the development of diabetes.  Through this project to understand this completely new concept, we hope to establish a novel therapeutic approach to cure obesity and diabetes.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

My long term area of interest is to understand the effects of oxysterols, which are cholesterol metabolites, on vascular disease such as atherosclerosis and vascular disease, or malfunction of blood vessel.  The function of adipose that stores excess fat in normal and abnormal condition is closely linked with the status of blood vessel.  Therefore, this project to understand the physiological effects of a certain oxysterol in the development of adipocytes, or fat storage cells, is in line with my long term area of interest and thus very important for me.

This award enables me to investigate my research of this unique molecule on the development of adipose tissue that causes obesity and consequent diabetes.  This awarded project plays a primary and critical role in my research efforts.

In what direction do you see the future of diabetes research going?

Diabetes is a complex disease, which encompasses many different factors.  To clarify each factors involved in the mechanisms leading to this disease is critical to establish a truly effective therapy on diabetes.  Therefore, basic research to understand the mechanism will gain much more importance than ever before.