A new study in mice indicates that overeating, rather than the obesity it causes, is the trigger for developing metabolic syndrome, a collection of heath risk factors that increases an individual's chances of developing insulin resistance, fatty liver, heart disease and type 2 diabetes.

How and where the body stores excess, unused calories appears to matter most when determining a person's risk of developing metabolic syndrome, researchers at UT Southwestern Medical Center suggest.

"Most people today think that obesity itself causes metabolic syndrome," said Dr. Roger Unger, professor of internal medicine at UT Southwestern and senior author of the study. "We're ingrained to think obesity is the cause of all health problems, when in fact it is the spillover of fat into organs other than fat cells that damages these organs, such as the heart and the liver. Depositing fatty molecules in fat cells where they belong actually delays that harmful spillover."

The study, available online, is to be published in a future issue of the Proceedings of the National Academy of Sciences. It is among the first to suggest that weight gain is an early symptom of pre-metabolic syndrome, rather than a direct cause.

"Obesity delays the onset of metabolic syndrome, but it doesn't prevent it," said Dr. Unger, who has investigated diabetes, obesity and insulin resistance for more than 50 years. "People who are obese or overweight are on the road to developing metabolic syndrome unless they stop overeating. Sooner or later, it will happen."

Currently about 50 million Americans suffer from metabolic syndrome. The exact cause of metabolic syndrome is unknown, but obesity and lack of exercise have been considered to be the primary underlying contributors to its development. Several studies in Dallas have shown that overweight patients with metabolic syndrome have increased fat levels in their liver, heart and pancreas.

Individuals with congenital generalized lipodystrophy - a genetic condition in which people are born with no fat cells in which to store fat - develop metabolic syndrome at an earlier age than people who are obese. They also develop more severe cases of metabolic syndrome earlier than their obese counterparts.

The goal of this study was to determine whether an individual's capacity to store fat in fat cells plays a role in whether they develop metabolic syndrome and type 2 diabetes and at what point that occurs.

For the study, the researchers compared mice genetically altered to prevent their fat cells from expanding when overfed to mice with no such protections against becoming obese. The normal mice got fat when overfed, but didn't develop signs of metabolic syndrome until about 7 weeks into the experiment, at about 12 weeks of age.

The mice engineered to remain slim, however, enjoyed no such "pre-diabetic honeymoon period," the study authors said. Some became seriously ill at 4 to 5 weeks of age and displayed evidence of severe heart problems and marked hyperglycemia by 10 weeks of age, a full 8 weeks before the normal mice displayed even minimal heart problems. The genetically altered mice also suffered devastating damage to heart cells and to the insulin-secreting cells in their pancreas.

"The genetically altered animals were perfectly normal as long as they were on a normal diet and not overfed. But as soon as we put them on a high-calorie diet, they got terribly sick very fast," said Dr. May-yun Wang, assistant professor of internal medicine at and lead author of the study.

She said the mice engineered to stay slim got sick quicker because the extra calories were not stored in the fat cells, the one place in the body equipped to store fat. Instead, fat was stored in other tissues, mimicking what happens in people with congenital generalized lipodystrophy.

"Recognition of this should encourage physicians and obese patients to pursue more aggressive interventions before they develop metabolic syndrome, rather than after the onset of disease, as is customary," Dr. Wang said.

The new results complement earlier findings by diabetes researchers at UT Southwestern who investigated why mice genetically engineered to be obese are at no more risk of developing metabolic syndrome than normal mice. The results of that study, which was led by Dr. Philipp Scherer, professor of internal medicine and director of the Touchstone Center for Diabetes Research, also suggested that it's not the amount of body fat, but where it is stored in the body that appears to matter most to health.

Dr. Unger said the most recent findings, like Dr. Scherer's, in no way condone obesity.

"It's best to eat only what you need to replace the energy you burn," he said. "But, if you eat more than you need, as most Americans do, it's better to put the surplus calories in fat cells than in the rest of the body because fat cells are designed specifically for fat storage. You won't be as trim, but you'll be healthier," Dr. Unger said.

The study results also imply that any gene that impairs the ability to store fat in the fat cells likely predisposes an individual to metabolic syndrome and type 2 diabetes, Dr. Unger said.

Researchers from Baylor University Medical Center and University Medical Center in Geneva also contributed to the study.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Department of Veterans Affairs, the Juvenile Diabetes Research Foundation and the Swiss National Science Foundation.

About Heart Disease

• Arrhythmias. Irregular, or abnormally fast or slow, beating of the heart. The heart beat is controlled by electrical impulses. When the timing or frequency of these electrical impulses are disrupted, arrhythmias develop. Some arrhythmias are quite serious. An example is ventricular fibrillation, a severely abnormal heart rhythm that causes death unless treated right away by providing an electrical shock to the heart (called defibrillation). Others are less severe but can develop into more serious conditions over time. A particular concern is atrial fibrillation. Atrial fibrillation is rapid, irregular beating of the upper chambers of the heart. The chambers can quiver instead of beating in a regular pattern. Blood is not fully pumped out of them and may pool and clot.
• Cardiomyopathy. A weakening of the heart muscle or a change in heart muscle structure. It often results in inadequate heart pumping or other heart function abnormalities. These can result from various causes, including prior heart attacks, viral or bacterial infections, and others.
• Congenital Heart Disease. Malformations of heart structures, present during pregnancy or at birth. These may be caused by genetic factors or by adverse exposures during pregnancy. Examples include holes in the walls that divide the heart chambers, abnormal heart valves, and others. Congenital heart defects can disrupt the normal flow of blood through the heart. Congenital heart defects are the most common type of major birth defect.
• Coronary Heart Disease (CHD)/ Coronary Artery Disease (CAD). Coronary artery disease (CAD), also called coronary heart disease (CHD) is a narrowing of the small blood vessels that supply blood and oxygen to the heart. CAD is the most common type of heart disease. CAD is the leading cause of death in the United States for men and women. According to the American Heart Association, more than 15 million people have some form of the condition. Coronary artery disease is caused by any problem with the coronary arteries that keeps the heart from getting enough oxygen- and nutrient-rich blood. The most common cause is atherosclerosis which occurs when fatty material and a substance called plaque builds up on the walls of your arteries. This causes them to get narrow. As the coronary arteries narrow, blood flow to the heart can slow down or stop The lack of sufficient blood is called ischemia, so coronary artery disease is sometimes called ischemic heart disease. The lack of blood flow can cause chest pain (stable angina), shortness of breath, irregular heart beats, called arrhythmias, and other symptoms.  Over time, CAD can weaken the heart muscle and lead to heart failure, a serious problem where the heart cannot pump blood the way that it should.
• Heart Attack. A heart attack, also called a myocardial infarction may occur when blood supply to the heart is severely reduced or completely blocked. When blood flow is restricted the heart muscle cells do not receive enough oxygen and begin to die. The more time that passes without treatment to restore blood flow, the greater the damage to the heart. This damage can cause irregular heart rhythms or even sudden cardiac arrest or stopping of the heart beat. Death can result. Coronary artery disease is the chief underlying cause of a heart attack. A less common cause of a heart attack is a severe spasm of a coronary artery that reduces the blood supply to the heart.
• Heart Failure. This may also be called congestive heart failure or chronic heart failure. Heart failure is a condition where the heart cannot pump enough blood and oxygen to meet the needs of other body organs. Heart failure does not mean that the heart has stopped, but that it cannot pump blood the way that it should. Heart failure is a serious condition. There is no cure for heart failure at this time, except a heart transplant. Once diagnosed, medicines are needed for the rest of the person's life. See our heart failure fact sheet.
• Peripheral Arterial Disease (PAD). Hardening of the arteries that supply blood to the arms and legs. PAD is usually the result of atherosclerosis, the buildup of plaque and narrowing of the arteries. Blood flow and oxygen to the muscles in the arms and legs can be reduced or even fully blocked. Painful leg muscles, numbness, swelling in the ankles and feet, and weak pulse in the feet are some of the signs and symptoms of PAD.
• Rheumatic Heart Disease. This condition is damage to the heart valves and other heart structures due to inflammation and scarring caused by rheumatic fever, which occurs from streptococcal infection. Heart disease is an umbrella term for a number of different diseases affecting the heart. Heart disease is a number of abnormal conditions affecting the heart and the blood vessels in the heart.

About Diabetes

Type 2 diabetes is also referred to as non-insulin dependent diabetes mellitus (NIDDM), or adult onset diabetes mellitus (AODM). Type 2 diabetes affects nearly 21 million in the United States and nearly 200 million people worldwide.

Type 2 diabetes is characterized by high levels of blood sugar, caused by the body's inability to utilize insulin to move blood sugar into the cells for energy. In type 2 diabetes, patients can still produce insulin, but do so relatively inadequately for their body's needs, particularly in the face of insulin resistance as discussed above. In many cases this actually means the pancreas produces larger than normal quantities of insulin.

Diabetes is a major cause of heart disease and stroke, as well as the most common cause of blindness, kidney failure and amputations in U.S. adults. 

About Metabolic Syndrome

• A quarter of the world's adults have metabolic syndrome
• People with metabolic syndrome are twice as likely to die from, and three times as likely to have a heart attack or stroke compared with people without the syndrome
• People with metabolic syndrome have a five-fold greater risk of developing type 2 diabetes
• Up to 80% of the 200 million people with diabetes globally will die of cardiovascular disease. This puts metabolic syndrome and diabetes way ahead of HIV/AIDS in morbidity and mortality terms yet the problem is not as well recognized.

• Heart disease
• Stroke
• Type 2 diabetes 

All of these conditions are associated with high blood insulin levels. The fundamental defect in the metabolic syndrome is insulin resistance in both adipose tissue and muscle. Drugs that decrease insulin resistance also usually lower blood pressure and improve the lipid profile.

• High blood pressure (hypertension). >130 mm hg / 35 mm hg
• Abnormal level of fasting blood glucose. > 100 mg/dl (or prediabetes which is between 100 - 125 mg/dl)
• Increased weight around the waist. (apple shape rather than pear shape). Typically a waist measurement (apple shaped) >35" for women, > 40 " for man.
• Elevated triglycerides. > 150 mg/dl
• Low HDL ("good") cholesterol. <40 mg/dl men, < 50 mg/dl