Continuous Changes in Brain's Appetite Center May be Key to Understanding Obesity

Researchers at Yale and Rockefeller Universities have found that ongoing changes in the appetite center of the brains of adult animals may explain why no successful medical strategies for long-lasting weight loss in humans have been developed.

The team, including senior author Tamas L. Horvath, associate professor of obstetrics and gynecology and neurobiology at Yale School of Medicine, found that brain circuitry which regulates eating is not hard wired, but changes its connectivity depending on nearby hormonal activities. Published in Science, the report focused on the fat-derived hormone Leptin, which regulates energy balance and is known for its hunger-blocking effect on the brain.

Horvath and his collaborators, including Jeffrey Friedman who discovered Leptin, analyzed the synaptic connectivity of the appetite center in transgenic mice. They correlated ultrastructure with electrophysiological measurements in obese and lean animals.

“Our observations suggest that this continuously changing wiring of the appetite center is a mandatory component in appropriate metabolism regulation, and we believe that this previously unknown plasticity is a key mechanism, failure of which may contribute to obesity,” said Horvath. “This also may explain the lack of successful medical strategies available for long-lasting weight loss.”

“The revelation of synaptic plasticity also raises the possibility that learning and memory is inherent to the feeding center in the hypothalamus, a process that so far has been associated mainly with higher brain regions,” Horvath added. “Equally intriguing is the question whether these metabolic signal-associated changes in wiring are limited to the hypothalamus or affect other central regions, such as the cortex or hippocampus.”

Horvath and his collaborators are currently studying the cellular mechanism of this synaptic plasticity and whether the phenomenon is present in primates. They are also testing whether re-arrangement of feeding circuits may be triggered by substances other than Leptin to diminish appetite in Leptin-resistant, obese patients.

Other authors on the study included Sabrina Diano and Marya Shanabrough in Yale’s Department of Obstetrics and Gynecology and Reproductive Sciences; and Shirly Pinto, Aaron G. Roseberry and Hongyan Liu, Xiaoli Cai and Jeffrey M. Friedman of Laboratory of Molecular Genetics and the Howard Hughes Medical Institute at Rockefeller University.

Citation: Science, Vol, 304 No. 5667 April 2004