News & Research

    Children's Hospital Boston, Boston, Massachusetts

Role Of ER Stress and ATF4 In Development Of Leptin Resistance

General Research Subject: Obesity

Focus: Obesity\Animal Models, Signal Transduction (Non-Insulin Action), Obesity

Type of Grant: Career Development

Project Start Date: July 1, 2009

Project End Date: June 30, 2014

Research Description

Funded by the Estate of Thomas R. Lee

Obesity is a fast growing problem and is one of the most serious threats to human health in the 21st century. Pharmacologic therapies to reduce appetite and increase energy expenditure would be useful in treating obesity, diabetes, and related metabolic disorders. Leptin is a fat-derived hormone that suppresses appetite through its action on the brain. However, it has not evolved as a drug due because the brains of the obese people becomes unresponsive to this hormone. The Ozcan laboratory in this proposal, by using molecular biology approaches and genetically engineered mouse models, aims to investigate the mechanisms that lead to leptin resistance in obesity. Understanding the molecular mechanisms of leptin resistance can help to develop new anti-obesity drugs and help to cure the obesity.

Reseacher Profile

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

The main focus of my laboratory is the relation between endoplasmic reticulum stress and development of insulin and leptin resistance in obesity. Obesity is one of the biggest risk factors for development of diabetes. Therapeutic modalities that will be effective against obesity will be invaluable, since treatment of obesity will also treat most of the obesity-associated diseases such as type 2 diabetes.   Leptin is a protein that is secreted from the fat tissue and suppresses the appetite through its action on the brain. Obese patients become resistant to leptin and molecular mechanisms of leptin resistance are poorly understood.  Recently we have demonstrated that a cellular organelle called Endoplasmic Reticulum (ER) experiences stress in the brains of the obese mice. The ER stress is communicated to the cell with various proteins and leads to development of leptin resistance.

Activating transcription factor 4 (ATF4) is one of those proteins that communicate the status of ER stress to the cell. Our preliminary findings indicate that ATF4 plays an important role in development of ER-stress induced leptin resistance. Our project by using molecular biology approaches and genetically modified mouse models will investigate the role of ATF4 in ER stress-mediated leptin resistance. Understanding the molecular mechanisms of leptin resistance might lead to development of new drug targets and ultimately, new drugs.

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

Our project aims to understand the molecular mechanisms of leptin resistance. Leptin was first discovered in 1995 and had a great promise to cure obesity due to its appetite suppressing effects in the leptin-deficient obese mice. However, soon after its discovery scientists have found that leptin cannot exert its appetite suppressing effects in the obese mice that were made obese by high fat diet feeding (equivalent of human obesity). The underlying reason for leptin to be ineffective in these obese mice and also in obese patients was found to be originating from the resistance that develops in the brains of the obese population against leptin.

Leptin can be used as a drug if the resistance to this hormone is reduced in the brain. This will help to cure the obesity. Considering the fact obesity is the main leading cause for development of type 2 diabetes, treatment of obesity will also lead to treatment of the most of diabetic patients and will also have a major impact in prevention.

We have recently demonstrated that increased endoplasmic reticulum stress plays a crucial role in development of leptin resistance in obesity and when agents that have ability to reduce ER stress is administered with leptin, it regains its ability to suppress the appetite and act as an anti-obesity agent.

Our project is aims to discover the molecular mechanisms of ER stress-induced leptin resistance. Success of our project will lead to identification of drug targets that will ultimately help us to develop new agents to block the effects of ER stress on leptin action. Our project may have a big impact on prevention of diabetes and other obesity-associated metabolic diseases.

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

I am a medical doctor who has devoted his career to obesity and type 2 diabetes research. Obesity is the most serious health problem in the world in the 21st century. It creates debilitating conditions such as type 2 diabetes, cardiovascular diseases, neurological problems and also associated with several cancers. During my medical school education, I have come across to lots of patients who were under the age of ten, but who were obese and had insulin resistance and type 2 diabetes.

For the first time in the US recent history, the expected life span has decreased due to a severe increase in the incidence of obesity and associated diseases such as type 2 diabetes. One of the biggest motivations for my self to be involved in obesity and diabetes research was to see that diabetes and obesity are not anymore adult diseases but they are seriously affecting the children. When I thought about the health problems that the current pediatric population will have due to obesity and diabetes at their very early ages, I decided to be a part of the effort that is spent to find a cure for these diseases and dedicated my career to diabetes research.

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

In the last decade there has been important advances in understanding of the diabetes. Now, we have better knowledge regarding the mechanism and reasons for development of diabetes. However, we still need to learn the detailed molecular mechanisms of this debilitating disease to find a cure. This can only come from the research efforts. I am optimistic and I strongly believe that we are close for a cure. In next two decades probably highly efficient therapies will be developed and the mechanisms for development of diabetes will be mostly solved.