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Originally published in the Spring/Summer 2005 Virginia Tech Research Magazine.

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Free radicals threaten fat cats and fad dieters

By Susan Trulove

Veterinarian Korinn Saker has demonstrated that immune function in overweight cats is compromised by rapid weight loss.

Clinical nutrition associate professor Korinn Saker with her "fat cat," Francois. Photo by John McCormick.

Janet Walberg Rankin, professor in human nutrition, foods, and exercise, led esearch on human dieters. One conclusion is that a popular high-fat diet causes inflammation.

Abigail Turpyn measured the amount of the inflammation marker CRP in the blood of women on the Atkins diet and women on a low-fat diet. Photo by Michael Kiernan.

Mary Whitlock and Janet Walberg Rankin are researching the inflammation-reducing effects of raisins and endorse the antioxidant benefits of grapes, berries, and apples. Photo by Michael Kiernan.

Studies looked at the benefits of specific foods. The humble raisin has antioxidant properties and may reduce the inflammatory response to a large meal.

"We are looking at foods, instead of pills, to disconnect obesity from health problems," Rankin says.

 

Weight loss is hard, but it is important to the long-term health of those who are overweight. As it turns out, weight loss can also be hard on you. Eat the wrong stuff and you could increase the risk factors weight loss is suppose to reverse — even while losing weight.

Your body is a complex chemistry set, and what you eat and don’t eat can affect you down to the cellular, even molecular, level. Inflammation and impaired immunity are the human equivalent of flames and bubbles in a test tube.

Human dieter research led by Janet Walberg Rankin, professor in human nutrition, foods, and exercise, implicates a popular high-fat diet as a cause of inflammation. Research with cats by veterinarian Korinn Saker has demonstrated that immune function is impacted by rapid weight loss. Saker and Rankin’s research goals are to find ways to lose weight without impairing health, while counteracting the cause of ill health in the chronically obese.

The Virginia Tech researchers agree that the culprit appears to be oxidative stress.

Oxidation, appropriately to this discussion of diet, is an example of too much of a good thing. We need oxygen to survive. Oxygen helps convert food into energy. However, in the oxidation process, some oxygen atoms lose electrons and become free radicals. The breakdown of fats produces more free radicals than does the breakdown of carbohydrates and proteins. These highly reactive atoms seek to correct their imbalance by robbing electrons from other atoms, which can interfere with cellular processes or damage such cellular components as DNA or the cell membrane. Oxidative stress is implicated in many chronic diseases, including cancer, diabetes, obesity, and compromised immune function. The defense is antioxidants - molecules that scavenge the free radicals.

From fat cats ...

"Immune cells need nutrients," says Saker, director of nutritional services and associate professor in clinical nutrition in the Virginia-Maryland Regional College of Veterinary Medicine at Virginia Tech. Through her research, she found that "acute weight loss is highly correlated with diminished function of immune cells; the cells have a difficult time responding to a disease."

Saker has two dogs and two cats, including a fat cat named Francois. “He is chronically obese. Francois has been on a weight reduction diet for five years and refuses to lose weight. I think he eats at the neighbor’s,” says Saker.

In humans, Francois’ condition, called metabolic syndrome, includes hyperglycemia, dyslipidemia, hypertension and, usually, cardiovascular compromise. "It's one step away from becoming diabetic in humans, and I believe the same is likely true with obese companion animals," Saker says. "Cats are an excellent model for human diabetes for several reasons. Type 2 diabetes, with it's associated hallmark decreased insulin secretion and insulin resistance, is common in both humans and cats. The cats' metabolism of fatty acids is similar to human's and obesity is a significant risk factor for Type 2 diabetes in both species."

Saker began her nutrition research before she became the owner of a fat cat. "I always wanted to be a veterinarian and I was interested in nutrition," she says. "My father had ALS and lived a fairly normal life for four years with a feeding tube. So I saw how nutrition impacts health and longevity of a critically ill patient." She earned a bachelor's degree at Purdue and master's degree at Clemson, both in animal nutrition, then her DVM at the University of Georgia before spending fi ve years in mixed animal practice. She then returned to academia to complete a residency in clinical nutrition at Virginia Tech, earning a Ph.D. in veterinary medical sciences. She is now president of the American Academy of Veterinary Nutrition.

Her research on how obesity affects health is focused on the role of fatty acid metabolism and immunity, in particular how oxidative stress and antioxidants are related to obesity and diseases closely related to obesity, such as diabetes.

And she is trying to determine a nutrition-based solution.

"I am trying to determine if a particular fatty acid, conjugated linoleic acid (CLA), will promote fat loss and help maintain lean body mass," she says. So far, she has observed that one form of CLA alters body composition.

Linoleic acid is an omega-6 fatty acid, a known essential fatty acid present in many vegetable oils. However, conjugated linoleic acid occurs primarily in beef and dairy products. CLA has a slightly different molecular structure than linoleic acid and, as a result, different nutritional benefits.

"Cows who eat high forage diets form CLAs in their meat and milk. And it can be formed synthetically," says Saker. The idea was to replace fat in the diet with CLA and feed a restricted calorie intake to obese patients - in her research, fat cats. "The thought was that the patient will only lose fat mass."

It worked.

Saker monitored the cats using dual-energy X-ray absorptiometry (DEXA), which measures lean-to-fat ratios. The same technology is often used to measure bone density in women. "We were able to prove that CLA maintained lean muscle and reduced fat."

Saker and her colleague, William Schoenherr, Hill's Pet Nutrition principal nutritionist, also looked at immune response and found the CLA diet helped sustain cell mediated immunity during weight loss.

"The problem is that such diets are expensive, so it hasn't gone far for companion animals," Saker says.

To translate the research into products for humans, Saker is involved in a USDA Sustainable Agriculture Research and Education (SARE)-funded, multi-location grazing study with North Carolina State, Clemson, and Virginia Tech, maintaining dairy cows on pasture all year and monitoring milk yield and CLA content, body fat-to-lean ratio, oxidative stress-antioxidant status, and immune parameters. "We will be analyzing the milk for CLA content as a nutrient-enriched protein source for humans," she explains. "We are also looking at how grazing management impacts year-round dairy cow health, economics of dairy production, and the ecological impact, or sustainability, on the land."

Meanwhile, a USDA-funded beef cattle study, spearheaded by Virginia Tech Animal Science Professor Joe Fontenot with researchers at Virginia Tech's Shenandoah Valley Agricultural Research and Extension Center and at West Virginia University's Willow Bend Demonstration Farm, is comparing cattle finished on grain with those finished on forage to determine immune response in the cattle, as well as the CLA content and antioxidant content of the meat.

"We will use the meat to formulate balanced diets for overweight pets," Saker says. "We will compare the CLA enriched diet to other diets and then look at the cat's immune response and how antioxidants in the diet effect weight loss in terms of preserving lean and losing fat tissue."

In the summer of 2004, the researchers compared a high-protein diet to a high-carbohydrate diet fed to obese cats. They enriched the oxygen in the cats' environment to simulate oxidative stress, which is when free radicals outnumber antioxidants, often resulting in cell damage.

Such oxidative stress is a real health risk for obese humans whose illnesses result in hospitalizations, Saker explains. For example, people hospitalized with heart problems are often put on oxygen, and anesthesia during surgery is delivered by oxygen.

The researchers were looking at whether a high protein or a high-carbohydrate diet would minimize oxidative stress. The results are that high-protein, low carbohydrate diets minimize oxidative damage to cells in obese patients, even during weight loss, at least in cats, Saker reports.

What about humans? People might have a hard time with a diet designed for cats.

... to overweight humans

Saker has been sharing her research process and results with colleagues in a group whose focus is oxidation. One of the group members is Janet Rankin.

Rankin has done much of her research on sports nutrition and was recently vice president of the American College of Sports Medicine. "But sports nutrition is not a huge public health problem," she says. "I did my Ph.D. research on obesity (University of California, Davis) and now the IGERT grant on oxidative processes has gotten me interested in returning to that topic from an exciting perspective." Researchers from three different colleges have been awarded a five-year, $3.2 million National Science Foundation Integrative Graduate Education and Research Traineeship (IGERT) award for a program that uses free radical and oxidation processes as the thematic basis for research and education at the chemistry-biology interface (www.chem.vt.edu/milesigert/).

Saker and Rankin proposed a number of studies in partnership with graduate students who were looking for research topics for doctoral dissertations. Abigail Turpyn, graduate student in human nutrition, food, and exercise, decided to look at the effect of the popular Atkins diet compared to a low-fat weight loss diet.

"We were interested in the Atkins diet because it recommends against everything that we know as nutritionists is good for you - fruits, grains, and even some vegetables," says Turpyn.

"There have been a lot of studies that show that cholesterol does not go up with the Atkins diet, and that, in the short term, weight loss is good," says Rankin. "However, we believed that those studies neglected to measure some important health indicators associated with oxidative stress and inflammation."

Low-carbohydrate, high-protein diets, particularly the Atkins diet, are low in antioxidants from fruits, vegetables, and grains, Rankin says. "And the Atkins diet is high in fat, which induces oxidative stress."

In fall 2003, Turpyn and Rankin recruited 29 overweight women. "We gave 14 the Atkins diet to follow, and 15 a low-fat diet similar to the Weight Watchers' diet," Rankin says. "The students were very involved in the four weekly sessions with the research subjects, taking blood samples, educating and supporting the subjects in their weight loss, and weighing them."

"We looked at body composition, antioxidant status, and inflammatory markers, which indicate if the body is in a state of chronic inflammation," says Saker. "Inflammation is typical in obese patients. It's bad because it has been shown that inflammation increases risk of cardiovascular disease."

The women on both diets - Atkins and low fat - lost weight. However, the researchers were looking at inflammation as indicated by C-reactive protein (CRP) in the blood, which is a better predictor of heart disease than cholesterol.

CRP is a special type of protein produced by the liver during episodes of acute inflammation, such as during a bacterial or viral infection. The most important role of CRP is its interaction with a group of proteins involved in immunological and inflammatory responses meant to attack the membranes of invading bacteria, killing them. Thus, inflammation helps with healing when there is an infection. But chronic low-level inflammation is bad. The condition has been linked to such cardiovascular risk factors as hypertension, diabetes, and elevated triglycerides. All the causes of chronic, low level inflammation are not known, but CRP levels are higher in most overweight people and typically fall with weight loss. Rankin is interested in whether the composition of the diet and types of foods consumed also affect CRP.

CRP in the case of infection is in the hundreds of milligrams per liter (mg/L). Normal is below 2 mg/L, while a level ndicative of low-level inflammation is only 3 to 4 mg/L, Rankin says.

In the Virginia Tech study, CRP in the women on the Atkins diet went up slightly, while it went down in the women on the low-fat diet. "It was interesting that we saw an increase in inflammation after just the first week on the Atkins diet," says Turpyn, "which is why we followed up with a one-week controlled feeding study."

"We hypothesize that the increase in the individuals on the high-fat diet was because of oxidative stress," Rankin says. The urine marker of oxidative stress the researchers measured did not change with the diets. However, because oxidative stress is difficult to measure, the group did a second study to further explore their hypothesis.

In the summer of 2004, the researchers did the second study to look more closely at antioxidant responses. "When you tell people to follow a diet, they sort of do. To have more control of the diet, we decided to do a controlled feeding for seven days," says Rankin. "We recruited 19 men and women and put them all on the Atkins diet for one week (63 percent fat, 6 percent carbohydrate, and 31 percent protein). We prepared all the food and they ate two meals a day on campus and took one home. To see if antioxidants mediated the changes we saw, we gave 10 subjects vitamin C and E as antioxidant supplements and nine subjects placebos."

The results were a 32 percent decrease in CRP for those who took the vitamins and a 50 percent increase in CRP for those who took the placebo. Interleukin 6 (IL-6), another chemical that indicates chronic inflammation in the body, decreased 15 percent and glucose decreased 19 percent for both groups. There was no change in the oxidative stress marker (urinary 8-epi) for either group.

"We conclude that an Atkins-like diet, with low carbohydrate and high fat, causes low-level inflammation, as indicated by CRP; but inflammation was prevented by antioxidant supplements, suggesting that the inflammation is due to oxidative stress. However, the lack of change in the oxidative stress marker, 8-epi, means we need more research with other markers to prove our hypothesis," Rankin says.

The good food approach

Like Saker, Rankin and her students are looking for dietary strategies to help overweight people while they diet - or even if they do not lose weight. "Although weight loss clearly reduces oxidative stress in obese individuals, few people successfully lose and maintain weight loss," says Rankin. "So we decided to identify easy to follow dietary approaches."

The researchers have begun a series of studies to look at the benefits of specific foods. For instance, human nutrition, foods, and exercise graduate student Mary Whitlock and Rankin are researching whether the modest, easily accessible raisin can benefit obese individuals with elevated CRP and IL-6. "We want to look at vascular function since people with high oxidative stress tend to have blood vessels that do not appropriately dilate and relax," Rankin says.

Such research would have some people eating raisins as part of their diet and some eating a placebo with the same calories. Oxidative stress would be introduced in the form of a high-fat meal, in addition to the raisins or placebo.

"Antioxidant supplements, red wine, and even Concorde grape juice reduce the inflammatory response to a big meal. We want to test the hypothesis that another form of the grape - the raisin - will too."

"We are looking at foods, instead of pills, to disconnect obesity from health problems," Rankin says.

Turpyn, who received an IGERT fellowship in fall 2004, is writing a journal article about her Atkins-diet research and assisting Whitlock and Rankin with the raisin study. Next, Turpyn plans to do research on the antioxidant benefits of whole grains in a high-fat diet. She expects to graduate in 2006. "The IGERT program has added classes to my schedule, but I'm getting a lot more out of my education," she says. Her goal is to continue to do research in a university setting and to teach.