Rat brain study helps UF researchers understand weight loss, gene therapy potential
GAINESVILLE, Fla. — A hormone that increases energy use and decreases appetite in mammals is helping University of Florida researchers learn how rats’ brains control weight loss and how gene therapy might one day help people stay slim effortlessly.
UF researchers used gene therapy to stimulate production of the hormone leptin in rats’ brains at four tiny sites believed to control weight loss, said Satya Kalra, a neuroscience professor with UF’s McKnight Brain Institute and College of Medicine.
The UF findings, reported in the November issue of the journal Endocrinology, showed that all four sites signaled the body to increase energy use; three also simultaneously reduced appetite.
“At one brain site, the medial preoptic area, leptin increased energy expenditure without affecting appetite, which means dieting isn’t necessary for weight loss,” Kalra said. “If we can develop weight-reduction therapies based on this finding, they would have the advantage of being independent of how much you eat.”
Statistics indicate Americans need all the weight-loss help they can get. The incidence of obesity in U.S. adults jumped from 12 percent in 1991 to 19.8 percent in 2000, according to the latest figures available from the national Centers for Disease Control and Prevention. Obesity increases the risk of cancer, diabetes and cardiovascular disease, and is responsible for at least 300,000 preventable deaths and almost $100 billion in health-care costs annually, according to the CDC.
The sites Kalra tested are located in the hypothalamus, a primitive part of the brain that regulates many basic body functions, he said. The sites were selected because previous research at UF and other institutions suggested they were involved in weight loss and activated by leptin.
“This study confirms that leptin activates two distinct pathways in the brain,” Kalra said. “One regulates energy expenditure, the other regulates appetite.”
Humans and other mammals process leptin in the hypothalamus but produce it mainly in fatty tissue, releasing the hormone when they eat. A small amount of leptin is produced in the hypothalamus, and previous UF studies in rats showed that gene therapy can increase production of the hormone there, helping the animals stay lean.
Leptin’s role in weight maintenance is still not fully understood, Kalra said. He and his wife, Pushpa Kalra, a physiology professor with UF’s McKnight Brain Institute and College of Medicine, have investigated leptin gene therapy for the past five years in about 25 studies. The current study was funded by a five-year, $1.9 million grant from the National Institutes of Health.
In the study, the Kalras and UF colleagues Michaela Bagnasco and Michael Dube conducted two experiments to evaluate about 100 healthy, adult female rats divided into weight-matched groups of six to eight rats each.
In each experiment, the researchers left two groups of rats untreated and injected rats in several other groups with a gene-therapy solution containing the apparently harmless adeno-associated virus, which had been altered to transmit either the gene that produces leptin or the gene that generates another harmless protein.
The solution was administered directly to one of the four sites in the hypothalamus, where individual brain cells took up the genes, Kalra said.
“Once the virus enters the cell and inserts the gene, the cell will produce leptin or the other protein for the rest of its lifetime,” he said.
Each rat’s food intake and body weight were monitored for 45 days. All rats were offered unlimited amounts of rat chow and water.
The results showed rats given the leptin gene in the medial preoptic area weighed 18 percent less than control rats but ate the same amount of food. Rats injected with the leptin gene in the other three areas lost weight and ate less than the control groups.
“We’ve located the sites of leptin action; now we need to trace the pathways the brain uses to communicate with the body for weight maintenance,” Kalra said.
Kalra cautioned the leptin gene therapy used in the study is years away from being tested in people because its safety and effectiveness must be evaluated thoroughly.
“We hope to begin research on nonhuman primates within two to three years and determine the dosages needed to obtain specific results,” he said.
Although application of the technology may be a long time coming, the UF study is a significant step forward, said leptin expert Dr. Rexford Ahima, an assistant professor of medicine at the University of Pennsylvania School of Medicine in Philadelphia.
This study proves that leptin can be delivered into discrete brain regions for long periods using a nonpathogenic virus, leading to sustained weight reduction,” Ahima said. “From a basic science perspective, it’s very important to have that proof.”