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FALL 2007
Discovering the Skinny on Fat
by Denise Horton

An Influential Hormone

In the early 1990s, researchers at Rockefeller University identified the hormone leptin as playing a significant role in body-weight regulation. Created in fat cells, leptin enters the circulatory system and travels to receptors throughout the body, including those found in the hypothalamus, the appetite center of the brain. It is believed that once leptin binds with receptors in the hypothalamus, signals of satiety are released, leading to appetite suppression.

Leptin is also involved in the loss of fat. When genetically obese mice that do not make leptin were given low doses of the hormone, they lost 30 percent of their body weight within two weeks. Researchers still don’t know how the weight loss actually occurs, but Harris is confident that there are factors beyond leptin that are necessary. For example, there may be still-unidentified hormones that are triggered after leptin reaches the brain, or they may be released when leptin binds with receptors elsewhere in the body.

Harris hopes that the results of two studies currently under way will shed light on both issues. One project focuses on preadipocytes, undifferentiated cells that will grow into fat cells. The other looks at mature fat cells. In both studies, with the assistance of UGA protein chemist Lance Wells in the biochemistry department, the Harris lab is separating various proteins out of blood serum that contains leptin. The preadipocytes and fat cells are then exposed to the blood serum. The results are expected to show whether leptin-laced blood serum affects lipid synthesis in mature fat cells or the proliferation of preadipocytes. It may also lead to the identification of other factors necessary for leptin-related fat loss.

A Reversal in Outcome

Harris’ research on leptin has shown that it can sometimes lead to weight gain rather than weight loss. In a study conducted with researchers at Georgia State University and the University of Pennsylvania, she and her colleagues gave leptin to rats whose forebrains had been surgically separated from their brain stems. These animals gained significant amounts of weight, while those given similar levels of leptin but whose brains were intact lost weight. The researchers’ results will soon be published in the journal Endocrinology. In another study, Harris showed that mice kept in a hot environment and fed a high-fat diet also gained body fat when they were treated with leptin. This work has recently been published in the American Journal of Physiology.

“Both of these studies indicate that if the leptin receptors located in the hypothalamus can’t be activated, but receptors in the brain stem are available, leptin leads to weight gain rather than weight loss,” she said.

In yet another study, Harris has discovered that rats fed a high-fructose diet quickly become leptin-resistant—they may have plenty of the hormone, but they cannot put it to use. This finding raises the idea that glucose and fructose follow different metabolic pathways that affect how leptin works. It may illuminate links between the human diet and obesity. “It’s worth noting,” says Harris, “that most people consume a large amount of fructose in their diet because the most common sweetener in processed food is high-fructose corn syrup.”

Effects of Stress

Although Harris’ team spends a great deal of time studying leptin, that’s not the only focus of their research. The scientists are also conducting a series of experiments on the impact of stress on body weight.

“I started studying stress because the loss of weight that occurs from it isn’t consistent with what we would have expected,” she said. “When a rat experiences extreme stress it loses weight. When the stress is relieved, the animal resumes its normal eating pattern, but it never makes up for the weight that was lost. That is, it never weighs the same as a rat that did not experience extreme stress.”

In a series of experiments, Harris and her colleagues have tried various ways of examining this phenomenon, such as giving the rats drugs that prevented them from losing weight. “It’s clear,” she concludes, “that there’s some sort of metabolic memory that the stress induces. After the stress has ended and we stop the drugs, the rats lose weight to the same level they would have without the drugs.”

Interestingly, Harris has determined that the weight-loss phenomenon is limited to extreme stress—caused, for example, by confining the animal in a small space. Mild stress—induced, say, by moving the rat to a new but amply sized cage, will cause it to lose a small amount of weight, which it usually regains within 24 hours.

“What these different responses demonstrate,” says Harris, “is that while extreme stress seems to impact the hypothalamus—the part of the brain that regulates food intake—mild stress primarily impacts the brain stem.”

Harris doubts that there’s any one key to body-weight regulation, not just in association with leptin, but overall. Other factors could trigger our bodies to become hungry, for example, or to raise our metabolism rates or lower them. Moreover, “I think an appreciation of social and behavioral factors is critical to understanding body weight regulation,” she said. “For instance, we know that people eat more in social situations; and that if you put M&Ms on someone’s desk they’ll eat more if the candies are in a clear container than in an opaque one.”

(Denise Horton is public relations coordinator in UGA’s College of Family and Consumer Sciences).