Florida researchers: Rats lose weight and keep it off through short-term dieting, long-term increase in energy expenditure

It’s a question as old as dieting itself: Do you have to keep eating less to maintain previous weight loss?

For a group of mildly obese adult rats, the answer was no, according to Florida scientists examining the effects of the “fat-sensor” hormone leptin on appetite suppression and calorie use. Results appear in this month’s issue of the journal Endocrinology.

Initially, the rats lost weight mainly through reduced food intake but kept it off by burning extra calories, even after food consumption returned to previous levels, said pharmacologist Philip Scarpace, Ph.D., a University of Florida professor and research director of the Geriatric Research, Education and Clinical Center at the Malcom Randall Veterans Affairs Medical Center in Gainesville.

“It’s too early to say whether these results are applicable to people,” said Scarpace, who led the study. “But they raise a possibility we all wish for — being able to diet for a short time, lose weight and then keep it off while going back to reasonable eating habits.

“Of course, you’d still have to increase your energy expenditure. In our study in rats, we used the hormone leptin to increase energy expenditure. In humans, at the present time, the most practical method to increase energy expenditure is through exercise.”

While the UF/VA study didn’t involve exercise, researchers looked at leptin’s two main functions — suppressing appetite and stimulating the body to burn more calories — and determined how these functions affected body weight. The study was funded by the Medical Research Service of the Department of Veterans Affairs and the National Institutes of Health.

Leptin is mainly produced in the fat tissue of humans and other mammals and is released during feeding to help regulate body weight. The hormone acts in the hypothalamus, a part of the brain that controls many basic body functions.

The researchers were able to evaluate leptin’s two functions separately by taking advantage of a phenomenon called leptin resistance, a decrease in leptin’s effectiveness believed to be caused by aging, obesity and other factors. By using gene therapy to add leptin-producing genes to the obese rats’ brains, the researchers were able to produce an oversupply of the hormone. This resulted in both reduced feeding and increased fat burning, but these beneficial effects waned over time.

“We observed the rats for more than four months and found that leptin’s appetite-suppressing effects lasted only about 27 days, but it promoted increased energy expenditure through fat burning for 83 days, more than three times as long,” said Scarpace. “In other words, the rats lost weight because they ate less food, but as their appetites gradually returned, they kept the weight off simply by using more energy.”

Scarpace found that the effects of leptin varied depending on how old or how overweight the animal was.

“The results we found here won’t apply equally in every situation,” he said. “We’ve demonstrated in previous studies that if you start with very obese animals, leptin will lose its effectiveness much faster than if you use animals that are only slightly obese.”

In the current study, Scarpace and UF/VA colleagues Yi Zhang, Ph.D., Eugene W. Shek, Ph.D., Victor Prima, Ph.D., Sergei Zolotukhin, Ph.D., Nihal Tumer, Ph.D., and senior biological scientist Michael Matheny conducted experiments in male rats that gradually became obese as they aged. The rats were 18 months old, considered middle-aged since their average life expectancy is 26 to 30 months.

In this study, 29 rats were divided into three groups. One group was injected with genetically modified adeno-associated virus, which served as a vector to deliver a rat leptin-producing gene, while two groups were given adeno-associated virus that had been altered to deliver a gene that makes a harmless protein. Once injected into a structure called the third cerebral ventricle in the brain, the adeno-associated virus entered individual brain cells and directed them to begin producing leptin or the other protein.

One of the groups administered the harmless protein served as controls, while the other was “pair-fed,” or given the same amount of food consumed by their counterparts in the group that received the leptin gene. The researchers monitored daily food intake and periodic whole body oxygen use as a measure of energy expenditure.

The pair-fed rats lost the same amount of weight as the leptin treated group, even though they burned fewer calories. This indicated that reduced food consumption predominately mediated the loss of body weight. However, after four weeks, all the rats resumed eating normal amounts of food, and only the leptin treated rats had elevated caloric burning. The pair-fed group regained the lost weight, but the leptin treated rats did not, demonstrating that the increase in energy expenditure alone in the rats that received the extra leptin gene was able to maintain the reduced weight even after food consumption returned to normal levels.

Scarpace said the team’s long-term goal is to find ways to increase energy expenditure in aged or obese animals, and, eventually, in obese people.

“Almost everybody experiences increased body weight and adiposity (fat content) as they get older,” he said. “It’s frustrating that even people who maintain reasonable eating habits throughout their lives often gain weight or body fat, and perhaps this line of research will help us understand the problem better.”