I have just found that 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.
Tart cherries -- frequently sold dried, frozen or in juice -- may have more than just good taste and bright red color going for them, according to new animal research from the University of Michigan Cardiovascular Center
I also found recent news that Tart cherries -- frequently sold dried, frozen or in juice -- may have more than just good taste and bright red color going for them, according to new animal research from the University of Michigan Cardiovascular Center.
Rats that received whole tart cherry powder mixed into a high-fat diet didn't gain as much weight or build up as much body fat as rats that didn't receive cherries. And their blood showed much lower levels of molecules that indicate the kind of inflammation that has been linked to heart disease and diabetes. In addition, they had significantly lower blood levels of cholesterol and triglycerides than the other rats.
The results, which were seen in both lean and obese rats that were bred to have a predisposition to obesity and insulin resistance, were presented Sunday at the Experimental Biology 2008 meeting in San Diego, CA by a team from the U-M Cardioprotection Research Laboratory.
In addition, the obese rats that received cherry powder were less likely to build up fat in their bellies -- another factor linked to cardiovascular disease. All the measures on which the two groups of animals differed are linked to cardiovascular disease and Type 2 diabetes.
The new findings build on results that were reported last year at the same meeting by the U-M team. Those data came from experiments involving lean rats that were prone to high blood pressure, high cholesterol and impaired glucose tolerance, but that received a low-fat diet with or without cherries. In that case, cherry-fed rats had lower total cholesterol, lower blood sugar, less fat storage in the liver and lower oxidative stress. However, it was unknown if these benefits would be observed in obesity-prone animals, or in animals fed a higher fat, western-style diet containing elevated saturated fat and cholesterol.
While it's still far too early to know whether tart cherries will have the same effect in humans, U-M researchers are preparing to launch a pilot-phase clinical trial later this spring. They note that if a human wanted to eat as many tart cherries as the rats in the new study did, they would have to consume 1.5 cups every day.
"These new findings are very encouraging, especially in light of what is becoming known about the interplay between inflammation, blood lipids, obesity and body composition in cardiovascular disease and diabetes," says Steven Bolling, M.D., a U-M cardiac surgeon and the laboratory's director. "The fact that these factors decreased despite the rats' predisposition to obesity, and despite their high-fat 'American-style' diet, is especially interesting."
The results were presented by E. Mitchell Seymour, M.S., a U-M research associate and the senior scientist on the project. "It was recently shown in humans that regular intake of darkly pigmented fruits like cherries is associated with reduced mortality from cardiovascular disease and coronary heart disease," says Seymour. "The heart-health benefits of these colorful fruits were sustained even when corrected for age and other health conditions. We're now invested in exploring the specific mechanisms of these benefits."
The experiments are funded by an unrestricted grant from the Cherry Marketing Institute, a trade association for the cherry industry. CMI has no influence on the design, conduct or analysis of any U-M research it funds.
The correlation between cherry intake and significant changes in cardiovascular risk factors suggests -- but does not directly demonstrate -- a positive effect from the high concentrations of antioxidant compounds called anthocyanins that are found in tart cherries. The anthocyanins are responsible for the color of these and of other darkly pigmented fruits.
The potential for protective effects from antioxidant-rich foods and food extracts is a promising area of research, says Bolling, who is the Gayle Halperin Kahn Professor of Integrative Medicine at U-M.
The team performed the study using 48 obesity-prone rats, half of which were obese, and a diet in which 45 percent of calories came from fat and 35 percent came from carbohydrates. All the rats were six weeks old when study began. For the next 90 days they were fed either a cherry-enriched diet in which cherries made up 1 percent by weight, or a diet that contained an equivalent number of carbohydrates and calories.
At the end of the study, the rats had blood tests for glucose, cholesterol and triglyceride levels, received DEXA scans to measure their body fat and to see where the fat had collected, and had tests for two plasma inflammation markers: TNF-alpha and interleukin-6.
These two molecules are related to the level of vascular inflammation, or immune-system reaction to blood-vessel walls, that is often seen in people and animals with cardiovascular disease. While inflammation is a normal process the body uses to fight off infection or injury, according to recent science, a chronic state of inflammation may increase the risk for a number of diseases.
The cherries were Montmorency tart cherries grown in Michigan, which is the nation's largest producer of tart cherries. They are different from the sweet Bing cherries that are often eaten fresh. Tart cherries have higher concentrations of antioxidant anthocyanins than sweet cherries.
By the end of the study, the rats that received the cherries had lower body weight, fat mass, total cholesterol, triglyceride, TNF-alpha and IL-6 than the rats that did not receive cherries. In all, TNF-alpha was reduced by 50 percent in the lean rats and 40 percent in the obese rats and IL-6 was lowered by 31 percent in the obese rats and 38 percent in the lean rats.
The obese rats that received cherries also had lower-weight retroperitoneal fat, a type of belly fat that has been associated with especially high cardiovascular risk and inflammation in humans.
In addition to Seymour and Bolling, the research team includes Daniel Urcuyo-Llanes, Ara Kirakosyan, Peter B. Kaufman, and Sarah K. Lewis of U-M, and Maurice Bennink of Michigan State University.
Even as the Cardioprotection Laboratory team continues its work in animals, U-M Integrative Medicine co-director Sara Warber, M.D., an assistant professor of family medicine at the U-M Medical School, is preparing to lead a pilot clinical trial of whole tart cherries in humans.
