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Winter 1997

Research Magazine > ARCHIVE > Spring 96 > Article

Tipping the Scales in FAT Research
by Judy Bolyard Purdy

In their battle of the bulge, overweight Americans vie with more than just a few unwanted pounds. The greater stakes are the increased risks of heart disease, diabetes and some kinds of cancer to which fat can contribute.

And since one in three Americans is obese, it's all the more important that scientists pinpoint how and why some people are more prone to put on pounds.

"Being overweight is a serious health risk," said Roy Martin, head of the University of Georgia's foods and nutrition department. "Obesity contributes to each of the seven leading causes of death in the United States, and they account for 80 percent of all mortalities."

Obesity -- which medical scientists define as tipping the scales at 20 percent or more of your recommended weight -- is as complex a problem as it is grave. Biological, psychological and even social factors can all contribute to the process by which your body stores energy in fat cells.

This intricate interplay forces scientists to explore many different ways the body and mind control our consumption of calories -- and how they all work together. For instance, the brain and digestive, nervous and circulatory systems all have a role to play in weight gain.

For more than two decades Martin has investigated the biological causes of obesity. He directs a team of researchers whose findings may one day lead to more effective ways to control or even prevent obesity.

Highlights of the team's findings on how the brain and body communicate about food consumption, stored fat and satiety (the "I'm full; stop eating" message) include:

  • When food is restricted, the body generates a powerful appetite stimulant called neuropeptide Y, or NPY for short. When fed a low-protein diet in the laboratory, young animals overeat and generate NPY.
  • The kind of fat you eat -- saturated versus unsaturated-- may influence what else you eat, including whether you choose high-carbohydrate foods.
  • Glucose levels in the brain may help determine how much you eat.
  • When underfed animals are allowed to "pig out," they gain weight until they reach a normal weight and then stop overeating -- unlike humans, who tend to keep putting on the pounds.
  • Fat cells are capable of generating a chemical that causes weight loss and suppresses appetite so much that it inhibits eating for two to three days.

The Brain Behind the Behavior

What, when and how much you eat begins in the brain. But just how your brain knows the body's metabolism and energy reserves is the key question for Martin's team.

One thing's for sure: The control mechanisms that help maintain a stable weight over long periods of time are extra-ordinarily precise.

"Nobody knows how, but the body has to communicate with the brain somehow and then make changes in the brain that tell it we've eaten enough or let's change our behavior because we're getting fat," said UGA research nutritionist Doug White. "It's probably not just one thing, either."

White studies chemical signals that relay information from the body to the brain. He is particularly interested in signals that cause predictable eating responses -- such as increasing the appetite -- and precisely where and how the brain receives those signals.

For example, one of these signals is a cortisone-like substance produced by the adrenal glands. Called GCC, or glucocorticoid, this protein molecule interacts with certain parts of the brain to influence food consumption and affect obesity.

"The adrenal glands are important in the expression of obesity," White said. "Whether rats are fat because of dietary or genetic factors, removal of the adrenal glands makes them thin."

Even genetically obese rats never become fat if their adrenal glands are removed. But give those same animals replacement doses of GCC, and they plump right up.

At first scientists thought the adrenal glands were over-producing GCC, causing the rats to be obese. White, however, found that faulty brain wiring was a more likely culprit.

His experiments showed that GCC stimulates certain brain areas to produce NPY, the most powerful appetite stimulant known. Quite naturally when the level of NPY is elevated, it leads to more food consumption and a bigger appetite.

White also has explored how various diets affect NPY production in the hypothalamus -- the brain region that regulates metabolic processes. He studied the effects of six diets -- two low in protein, two low in fat and two low in carbohydrate content -- but all containing the same number of calories.

"Our hypothesis was that restricting carbohydrates would stimulate an increase in NPY synthesis, but that's not the way it turned out," White said. "When protein was restricted, the levels of NPY [production] increased but there was no effect with fat- or carbohydrate-restricted diets."

With funding from the U.S. Department of Agriculture, White also compared the effects of low-protein diets (10 percent protein instead of the usual 20 percent) on young versus mature rats. While the young rats overate, the mature ones maintained their former levels of food intake.

"Young animals are still growing, and they have a higher protein requirement than mature animals," he said. "The young rats may be overeating in calories to get enough protein."

His findings also may shed light on the link between nutrition and obesity in some children.

"This research could have implications in dietary requirements, but it's still too early to tell," he said.

White is now conducting experiments to test another prediction: Adults may burn excess protein as fuel instead of using it for growth. If so, the protein would break down into waste products like ammonia. When ammonia circulates to the brain, it sets off a chain of events that lowers NPY production in the hypothalamus.

The Sugar Link

Glucose levels in the hypothalamus may provide another clue to food intake and obesity. The idea, first advanced four decades ago by Harvard researcher Jean Mayer, is that the brain regulates stored energy and feeding behaviors based on blood sugar levels. But the techniques to test the theory weren't available until recently.

Martin's team has shown that when animals fast, they use fat for fuel. But when they overeat, they burn glucose -- a simple sugar. The scientists used a glucose blocker to prevent glucose in the blood from being used by cells. Even though the blood carried plenty of glucose, the brain was tricked into perceiving a shortage and responded by producing more NPY, which sent the signal to eat.

"Things like food deprivation and exercise decrease the glucose levels and increase NPY," White said. "Blocking glucose increases NPY levels. So glucose could be a common thread that leads to increases in food intake and obesity."

The researchers now suspect that the brain's mechanism for detecting glucose may be very similar to the way the pancreas detects blood sugar levels.

"This idea ties a lot of information together," Martin said. "We're finding the way the brain senses glucose could be the same way cells in the pancreas sense glucose. Other labs have shown that other areas of the brain also have these particular cells, and it turns out these areas may be involved in feeding behavior."

Regulating Food Preference

It might be simpler to understand eating behaviors if the hypothalamus were the only brain region involved. But that's not the case.

Gaylen Edwards, a UGA professor of physiology and pharmacology, studies the brain stem, the region at the base of the brain. Unusual things happen to appetite when you manipulate this region. That's because the brain stem not only influences how much we eat, but also which foods we prefer.

"All the nerves from the stomach, the intestines and the liver first stop in the brain stem," Edwards said.

When Edwards made tiny lesions to prevent the nerves from continuing their communication, lab rats altered their diets dramatically and lost weight.

"Up to two hours after surgery, they choose very sweet foods like vanilla wafers and eat enormous quantities of them. But over a 24-hour period, they switch to a protein-rich diet," he said. "It's a very dramatic change and we are not sure yet how to interpret that."

But Edwards said he hopes to get a clearer picture from his current studies, which trace the effects of certain drugs that interfere with specific neurotransmitters. "If we can understand how [brain] systems function and which neurotransmitters are important, we can then start to work on therapies for obesity that will be effective," he said.

That's because rats and people are alike in many ways. For example, sometimes rats just can't resist overeating when abundant supplies of tasty sweet morsels are available, said UGA assistant research scientist Barbara Grossman.

With funding from the National Institutes of Health, Grossman has shown that rats may become obese when allowed to feed freely on diets rich in either carbohydrates or fats. Her findings on how fat consumption influences food selection also may shed light on why some obese people crave carbohydrates.

Taste Isn't an Issue

Grossman carried out several experiments on how fat in the diet affects food preferences. She gave rats of all ages and both sexes either unsaturated fat (like corn oil) or saturated fat (like vegetable margarine or tallow) to see which foods they would choose. To avoid the influence of the fat's taste on food selection, she bypassed some animals' taste buds.

Regardless of age, sex or how they were fed, the results were always the same. Those that received unsaturated fat chose the high-carbohydrate, low-protein fare; the saturated-fat group preferred just the opposite: a low-carbohydrate, high-protein diet.

"Different types of fat will affect subsequent appetite," she said. "And this can happen within two hours. It's a very quick response."

Grossman also has studied the liver's role in diet selection. "The liver generates a lot of signals that influence eating behavior. It's the first organ that receives information from your diet," she said. "Most of the nutrients you eat go to the liver first to get processed."

She used a chemical to block the lab animals' ability to use fat as a food source. Regardless of whether the diet contained unsaturated or saturated fat, the rats chose a high-carbohydrate diet. The same held true when the nerve between the liver and the brain was inactivated, indicating the brain received feedback from the liver on diet selection and fat consumption.

The nerve carries a "unique signal from saturated fat metabolism [that] induces protein consumption at the cost of carbohydrates," Grossman said. "Maybe there is some unique difference in metabolism between saturated and unsaturated fat. I haven't figured that out yet."

Much of the recent obesity research in Martin's lab has piggybacked on the findings of former UGA scientists and doctoral students like Ruth Harris. Now a research scientist at Pennington Biomedical Research Center in Baton Rouge, La., Harris showed in the early and mid-1980s that overfed animals are able to adjust food intake and body weight.

After restricting food intake in normal-weight rats for several days, Harris let them eat their fill. Not surprisingly, they overate. But they stopped overeating when their weights returned to prerestriction levels.

"Humans do the same thing after they diet," Martin said. "Ninety-five percent of people who start a weight-loss program will return to their original weight within five years."

Harris overfed normal-weight rats until they became obese. As their body fat climbed to 30 percent from 10 percent, they gained weight according to a very distinct pattern. But when overfeeding ceased, the rats reduced their food intake until both their weight and body fat returned to pre-experiment levels.

"The animals' bodies seemed to recognize' that they had gained too much weight and too much body fat, and they reduced their food intake until their body weight was back to normal," Martin said.

In another study, Harris proved that a substance produced by the body and carried in the bloodstream regulates food intake and reduces body fat. Martin called those experiments "pivotal" in advancing the understanding of food intake on weight gain and body fat. "It appeared that a circulating factor was reducing body-fat content by inhibiting fat synthesis rather than by breaking down fat stores," he said.

Signals of Satiety

In 1953, British scientist Gordon Kennedy proposed that the brain monitors some signal from fat that helps the body maintain a fairly constant fat percentage. For almost four decades scientists searched unsuccessfully for a satiety signal from fat cells. Then, in 1989, Marty Hulsey, a doctoral student and now an assistant research scientist in Martin's lab, conducted experiments that provided evidence for a satiety signal from fat -- or adipose -- tissue.

Hulsey separated fat into five different categories based on the weight of proteins found in the fat and discovered that the mid-range proteins inhibited eating and caused weight loss in lab animals. Hulsey dubbed this potent but unknown appetite inhibitor ASF, or adipose satiety factor.

In later experiments Hulsey showed that ASF even suppresses feeding activity when food intake has been restricted for two to three days.

"It took almost three days of restricted feeding to overcome the effect of ASF, so it was pretty powerful," Hulsey said.

"The satiety signal may be an important link in understanding how the body and brain communicate energy status to maintain a remarkably consistent weight throughout a lifetime," Martin said. "Such a signal could be a key factor in weight control."

Hulsey cautiously decided not to publish his results until he had determined that the activity was not just a side effect.

"A pivotal concern with a potential satiety factor is the behavioral specificity of the effect," Hulsey said. "Is it suppressing feeding because it's a natural satiety mechanism -- something that makes the rat feel full -- or is it simply making the rat sick? You can't ask the rat whether it feels ill so you do a taste aversion test."

Taste aversion -- one of three tests Hulsey applied -- uses a saccharin solution administered with either ASF or lithium chloride, a chemical that makes rats mildly sick. When rats get sick after drinking the sweet solution, they won't go near it again. The ASF treatment didn't make them avoid the saccharin, which meant the weight loss was not a side effect of the experiment.

"We still had a hard time getting the results past the [scientific journal] reviewers," he said. "They just didn't believe it because people had looked for so many years for something like this, and I was just a graduate student at the time."

After publishing his results, Hulsey won a highly competitive and prestigious University Exploratory Research Grant from Proctor and Gamble Inc. to find the active ingredient. But there was a problem that no one could foresee: The mixture contained more than 80 proteins, a stumbling block for any scientist with limited resources.

At the same time, scientists at Rockefeller University were doing similar research, except they had started with a gene and worked their way up to a protein. In November 1994, they announced their discovery of a mouse gene that made a protein that reduced body fat. Named the "ob" protein, it may hold another key to understanding genetic obesity.

"We think Marty Hulsey was very close to being the one to discover the ob protein," Martin said. "ASF suppressed food intake and body weight exactly like the ob protein, but it has many proteins in it and you don't know which one is the active one."

Martin's team now is preparing to study the ob protein. With help from Ron Makula, director of the UGA fermentation plant, they're using bacteria to grow large quantities of the ob protein for a variety of experiments. For example, Hulsey wants to compare it to ASF to see if they are one and the same protein. White said he believes the ob protein works through a neural transmitter and plans to test its effects on NPY production. Grossman intends to see if the ob protein acts through the nerve between the liver and brain to affect appetite and weight.

The entire team of scientists working with Martin on obesity research includes UGA faculty, research scientists and graduate students from four of the university's 13 colleges as well as a small complement of investigators at the USDA Richard B. Russell Agricultural Research Center.

Together they take a two-pronged approach to understanding obesity. One group probes the biological hows and whys of fat cell development (see related story on page 14), while the other studies the internal mechanisms between the brain and body that determine when, what and how much to eat.

"When I began this research I wanted to understand what causes the body to produce and store fat in the first place, so that we might be able to control fat and thus reduce the health risks associated with obesity," Martin said.

For the more than 80 million Americans who are considered obese, the results of this research may ultimately be a step in finding ways to live healthier lives.


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