News & Research

Johns Hopkins University Baltimore, Maryland

Obesity, heart failure and metabolism: Role of leptin in cardiac protection

General Research Subject: Obesity

Focus: Integrated Physiology\Muscle, Obesity\Animal Models, Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis

Type of Grant: Basic Science

Project Start Date: January 1, 2010

Project End Date: December 31, 2012

Research Description

The 'fat hormone' leptin regulates energy balance and fat stores, but also has effects on the heart. Leptin provides the heart with some protection, which is lost in patients with diabetes and obesity, but it is not known exactly how this works. One of the sympathetic nervous system receptors, beta3-adrenoreceptors (B3-AR), depends on normal leptin function to work properly. Mice without B3-AR develop abnormal thickening of the heart muscle and damage from free radicals. Thus, main goal of this project is to show that leptin's protective effects are due to the presence of functional B3-AR in the heart.

1: How does interrupting leptin affect the development of abnormal heart function, and what is the role of B3-AR?

The investigator will identify which leptin and B3-AR signaling pathways are affected by inducing heart failure in 4 mouse models: normal mice, mice lacking leptin, mice with nonfunctional leptin receptors, mice with diet-induced obesity and a special mouse that is missing leptin receptors only in the heart.

2: Is B3-AR dependent on the presence of leptin to protect the heart? 

Using heart muscle cells in a dish can help us figure out whether the effects we see in a live animal are due to direct effects in the heart muscle or due to effects from other parts of the body. For these experiments, the investigator will study whether B3-AR in heart muscle cells is affected by leptin, whether leptin itself can protect the cells, and if this protection is lost when B3-AR is blocked.

Researcher Profile

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

This project covers research primarily in the diabetes-related area of obesity. Obesity is a major epidemic in the United States and throughout the developed world. Over 60% of the U.S. population is now overweight or obese, which is associated with greatly elevated risk of developing type II diabetes, as well as increased morbidity and mortality from many common cardiovascular diseases. Heart failure risk increases greatly with obesity and even more so in the presence of diabetes. Our work is aimed specifically at describing the role of the obesity-related hormone leptin and its signaling pathways in the development and prevention of heart failure. In the course of this project, we expect to discover novel approaches to treating obesity and diabetes-related heart disease and preventing the development of heart failure in these populations.

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

We have already gotten a lot of clues from our earlier studies about one of the signaling pathways that seem to be related to obesity-related hormone signals in the heart. Throughout this project we expect to develop a new approach to treating obesity and diabetes-related heart disease and preventing the development of heart failure in these populations. In particular, a shortage of signal through receptors called beta-3 adrenergic receptors, or B3AR for short, may be responsible for some of the cardiac dysfunction that occurs in obesity and diabetes. We have found that stimulating these receptors has a protective effect and can prevent the development of heart failure. Our experiments will test whether these same drugs will protect the heart in several different models of 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? 

There is substantial evidence that obesity confers increased risk for structural heart disease independently of associated conditions such as hypertension and diabetes. There is mounting evidence that leptin is intricately involved in obesity-related cardiovascular disease. Defining the precise mechanism of action and identifying the extensive hemodynamic and structural effects on the heart will be paramount to our understanding of obesity-related cardiac hypertrophy and heart failure.

As both a clinician and a scientist, ultimately translating basic research into clinical practice is of utmost importance. As a heart failure and transplant cardiologist, I see so much heart disease related to diabetes and obesity that it is unquestionably the most important area of research in my subfield. This independent research award is critical to my success. With the generous 3 years of support, we will be able to develop this project fully and also realize the therapeutic potential of some novel new agents. At a time when federal funding is very tight, foundation awards such as the ADA Basic Research Grant become ever so much more important to provide ongoing support for 'up and coming' laboratories to pursue groundbreaking research.

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

Diabetes research is heading toward developing new areas of prevention and treatment, both for diabetes itself and for highly related conditions such as obesity. I believe that first basic science and ultimately translational applications of brand new approaches will hold the keys to developing novel therapeutic modalities to treat diabetes and obesity, as well as prevent the development of complications. In particular, cardiovascular disease is the leading cause of death in diabetic patients, and continued focus on preventing and treating heart disease in diabetic patients may be our best bet to improving life span and quality of life for our patients.