Persistent Overeating By The Obese Generates Massive Free Radical Load, Initiating Artery Disease

ScienceDaily (Jan. 22, 2001) — BUFFALO, N.Y. -- Endocrinologists at the University at Buffalo have pinpointed one of the mechanisms that place the obese at higher risk of atherosclerosis and subsequent heart attack.

Their study, published in the January issue of The Journal of Clinical Endocrinology and Metabolism, shows that persistent overeating in the obese exposes them to excessive oxidative damage from free radicals, the hyperactive oxygen molecules that damage arterial walls and initiate the accumulation of fatty deposits that eventually inhibit or block blood flow to the heart.

Moreover, the researchers found that severely restricting caloric intake decreased the production of free radicals by more than 50 percent, lowering the risk of developing heart disease without medication.

"Our research has shown for the first time that the obese carry a massive oxidative load," said Paresh Dandona, M.D., UB professor of medicine and primary author on the study. "This oxidative load causes the kind of changes in the blood stream that make obese people prone to heart disease.

"We've also shown for the first time that diet restriction alone can change their risk," he said. "Taking a pill is easier, but lifestyle change is just as effective and should be considered."

Dandona and colleagues at the Diabetes-Endocrinology Center of Western New York at Kaleida Health, which Dandona heads, set out to determine whether the generation of free radicals and other indices of oxidative damage decrease as a result of short-term calorie restriction and weight loss.

Their study subjects were nine obese nondiabetic men and women who were taking neither antioxidant vitamins nor medication for heart disease. Their weight ranged from 183 lbs. to 360 lbs., with a mean body mass index (BMI) -- a ratio of weight to height -- of 40.7. An individual with a BMI over 30 is considered obese.

After taking fasting blood samples, researchers placed the participants on 1,000-calorie diets, consisting of a 200-calorie commercial liquid diet drink for breakfast and lunch and a home-cooked 600-calorie dinner. They remained on the diet for four weeks, returning to the clinic weekly to be weighed and provide fasting blood samples. Participants were asked to maintain their normal level of physical activity.

At the end of four weeks, participants had lost an average of 10 pounds. Analysis of blood samples showed a marked decrease in both markers of oxidative damage and the generation of free radicals. The more than 50 percent fall in free radical concentrations was accompanied by a significant decrease in markers of oxidative damage to lipids, proteins and amino acids.

"This finding is important because it represents a dramatic reversal in the cardinal processes affecting atherogenesis without the use of any drug or antioxidant," Dandona said. "Despite the wide variation in BMI, the changes were consistent and therefore are intrinsic to the process of dietary restriction and weight loss."

All participants gained weight after the four-week intervention, and at three months post-study, the concentration of free radicals and indices of oxidative damage were higher than at its inception, the researchers found.

Additional authors on the study are Ahmad Aljada, Ph.D., UB research assistant professor of medicine; Richard Browne, Ph.D., UB research instructor in the Department of Social and Preventive Medicine; and Priya Mohanty, Husam Ghanim, Wael Hamouda, Anu Prabhala, Aqeela Afzal and Rajesh Garg, doctoral students working with Dandona.

The study was supported in part by the William G. McGowan Charitable Fund.

Adapted from materials provided by University At Buffalo.

University At Buffalo (2001, January 22). Persistent Overeating By The Obese Generates Massive Free Radical Load, Initiating Artery Disease. ScienceDaily. Retrieved January 6, 2008, from http://www.sciencedaily.com­ /releases/2001/01/010117075128.htm

How Eating Less Might Make You Live Longer

ScienceDaily (Mar. 6, 2007) — Caloric Restriction in non-obese people translates into less oxidative damage in muscle cells, according to a new study by Anthony Civitarese, Eric Ravussin, and colleagues (Pennington Biomedical Research Center). As oxidative damage has been linked to aging, this could explain how limiting calorie intake without malnutrition extends life span.

A calorie-restricted diet provides all the nutrients necessary for a healthy life but minimizes the energy (calories) supplied in the diet. This type of diet increases the life span of mice and delays the onset of age-related chronic diseases such as cancers, heart disease, and stroke in rodents. There are also hints that people who eat a calorie-restricted diet might live longer than those who overeat. In addition, calorie-restricted diets beneficially affect several biomarkers of aging, including decreased insulin sensitivity (a precursor to diabetes). But how might caloric restriction slow aging? A major factor in the age-related decline of bodily functions is the accumulation of "oxidative damage" in the body's proteins, fats, and DNA. Oxidants--in particular, chemicals called "free radicals"--are produced when food is converted to energy by cellular structures called mitochondria. One theory for h ow caloric restriction slows aging is that it lowers free-radical production by inducing the formation of efficient mitochondria.

Civitarese and colleagues enrolled 36 healthy overweight but non-obese young people into their study. A third of them received 100% of their energy requirements in their diet; the caloric restriction (CR) group had their calorie intake reduced by 25%; and the caloric restriction plus exercise (CREX) group had their calorie intake reduced by 12.5% and their energy expenditure increased by 12.5%. The researchers found that a 25% caloric deficit for 6 months, achieved by diet alone or by diet plus exercise, decreased 24hr whole body energy expenditure (i.e. overall calories burned), which suggests improved mitochondrial function. Their analysis of genes involved in mitochondria formation indicated that CR and CREX both increased the number of mitochondria in muscle. Both interventions also reduced the amount of DNA damage--a marker of oxidative stress--in the participants' muscles.

The researchers also examined gene expression in the study participants. In yeast, worms, and flies the activation of the Sir2 gene increases life span and regulates cellular metabolism. An important question is whether caloric restriction can regulate SIRT1 (the mammalian equivalent of Sir2) in humans. Civitarese and colleagues found that indeed fewer calories can improve whole body metabolism in conjunction with an increase in SIRT1 gene expression in skeletal muscle. These results raise the possibility that SIRT1 may contribute to more efficient metabolism, less oxidative stress, and increase longevity in humans as it does in lower organism.

The results suggest that even short-term caloric restriction can produce beneficial physiological changes leading to improved health. Whether caloric restriction and the associated health benefits can be sustained over longer term remains to be established in humans.

Citation: Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, et al. (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 4(3): e76. (http://dx.doi.org/10.1371/journal.pmed.0040076)

Adapted from materials provided by Public Library of Science.

Public Library of Science (2007, March 6). How Eating Less Might Make You Live Longer. ScienceDaily. Retrieved January 6, 2008, from http://www.sciencedaily.com­ /releases/2007/03/070305202936.htm

Rate Of Cellular Energy Production Lower In Persons At Risk For Type 2 Diabetes

ScienceDaily (Aug. 26, 2005) — New Haven, Conn.-The rate of insulin-stimulated energy production is significantly reduced in the muscles of lean, healthy young adults who have already developed insulin resistance and are at increased risk of developing diabetes later in life, according to a Yale School of Medicine study.

The new research by Gerald Shulman, M.D., professor of internal medicine, endocrinology, and senior author of the study, indicates that a decreased ability to burn sugars and fats efficiently is an early and central part of the diabetes problem. The new data also suggest that the basic defect lies within the mitochondria, which are the energy factories inside cells that produce most of the chemical power needed to sustain life.

The young adults studied by the research team are the offspring of parents who have type 2 diabetes, adding support to the idea that the risk can be inherited and that the problem begins well before diabetes symptoms become evident. The researchers observed that the mitochondria in the subjects' muscle cells responded poorly to insulin stimulation. Normal mitochondria react to insulin by boosting production of an energy-carrying molecule, ATP, by 90 percent. But the mitochondria from the insulin-resistant people they tested only boosted ATP production by five percent.

Among their findings was also evidence for a severe reduction in the amount of insulin stimulated phosphorus transport into the muscle cells of the insulin-resistant participants. This also points to a dramatic defect in insulin signaling and may explain the observed abnormalities in insulin-stimulated power production in the insulin-resistant study subjects. Phosphorus is a key element in the mithochondrion's complex energy-production process.

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The co-authors were Kitt Petersen and Sylvie Dufour.

PLoS Medicine 2: www.plosmedicine.org (September 2005)

Adapted from materials provided by Yale University.

Lots Of Low-fat Food Is Better Than Small Portions Of High-fat Food

ScienceDaily (Feb. 6, 2004) — Dutch research has shown that a diet of low-fat products is better than smaller portions of normal high-fat food for preventing diabetes in obese people. Mice put on a low-fat diet were more sensitive to insulin than mice that received the same amount of energy in the form of high-fat food.

Martin Muurling put obese mice on different diets in which the total energy intake and the final body weight were the same. He then studied the effect of these diets on insulin sensitivity.

Mice that received just low-fat products were more sensitive to insulin than mice that ate small portions of high fat food. A low-fat diet is, therefore, a more effective remedy for diabetes than eating less calories.

Muurling also discovered that in mice, the consumption of fish oil had no positive effects whatsoever on reduced insulin sensitivity. From this he concluded that a diet with fish oil cannot prevent or remedy diabetes in the case of somebody who is already less sensitive to insulin due to a high-fat diet.

Clinically obese people sometimes suffer from a certain form of diabetes, type II diabetes mellitus. This is because far more fatty acids are released from the adipose tissue during obesity. These fatty acids can reduce the functioning of the beta cells in the pancreas as well as the sensitivity of various tissues to insulin.

Fat accumulation in adipose tissue is less harmful than fat accumulation in organs such as the liver and muscles. Treatment methods that lead to a reduction of fat accumulation in the liver and muscles might also remedy type II diabetes mellitus in obese patients.

In diabetics, the regulation of the blood glucose level and the transport of glucose from the blood to tissue cells are disrupted. This is due to either an inadequate production of insulin or the insulin available not being effective enough. Obesity and type II diabetes mellitus will probably be the health problems of the 21st century, as the number of obese people has risen sharply over the last few decades.

The research was funded by the Netherlands Organisation for Scientific Research.

Adapted from materials provided by Netherlands Organization For Scientific Research.