SUNDAY, Aug. 10, 2008 (HealthDay News) -- Researchers have developed a strain of mice resistant to diet-induced obesity.
The findings could one day lead to possible drug treatments for obesity in people. They also shed light on the brain circuitry that controls energy homeostasis -- the balance between how much energy (i.e., food) an animal takes in and how quickly it burns that energy.
Dr. Julio Licinio, a professor of psychiatry and behavioral sciences at the University of Miami Miller School of Medicine, called the research a "technological tour de force."
Dr. Bradford Lowell, associate professor of medicine at Harvard Medical School, led the study, which was published online Aug. 10 in the journal Nature Neuroscience.
According to lead study author Qingchun Tong, most research into energy homeostasis has involved what scientists call genetically encoded neuropeptides, rather than small molecule neurotransmitters.
Neurotransmitters "have been postulated to play a very important role in neurocommunication, but in this field, essentially no critical studies have been performed to address this issue," Tong said. "So I set up an experiment to create an animal model in which a particular group of neurons in the brain couldn't release a small neurotransmitter, and by examining those animal models, I could know the function of those molecules."
Tong and Lowell focused on one neurotrasmitter in particular, called GABA (gamma-aminobutyric acid). They developed transgenic, or mutant, mice that lacked the ability to release GABA in a subset of brain cells in the hypothalamus -- the brain region that controls processes such as hunger, thirst and body temperature.
On a normal diet, the normal and mutant mice weighed roughly the same, with mutant mice weighing slightly less. On a high fat diet, however, the mutant mice gained far less weight than the normal mice, even though the two groups ate approximately the same amount of food. The reason: The mutant mice were burning energy at a faster rate, the researchers said.
"We found that the mice without GABA release from AgRP neurons have increased energy expenditure and are resistant to diet-induced obesity," Tong said.
These transgenic mice were also resistant to the effects of the hormone ghrelin, which governs hunger. When normal mice were given ghrelin, their food intake increased. In the mutant mice, however, that effect was dampened, Tong said.
Finally, the researchers shed some light on the brain cell networks controlling energy homeostasis. They found that another group of neurons in the hypothalamus, called pro-opiomelanocortin (POMC) neurons, receive the GABA signal from AgRP neurons.
"The function of AgRP neurons is probably to reserve the energy for maintaining life," Tong said. "So if the animal doesn't have enough food, the animal should have some strategy to preserve energy, and this group of neurons, by releasing GABA, restrains energy expenditure to maintain enough energy to survive under the conditions in which food is not readily available."
According to Licinio, these findings underscore the importance of the GABA neurotransmitter in regulating the relationship between food consumed and energy expended. "I think it makes the role of GABA in obesity much more relevant than previously thought," he said.
Of course, as with all animal studies, it remains to be seen whether the findings can be repeated in humans.
For more on obesity, visit the U.S. Centers for Disease Control and Prevention.
SOURCES: Qingchun Tong, Ph.D., Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; Julio Licinio, M.D., professor, psychiatry and behavioral sciences, and associate dean, University of Miami Miller School of Medicine; Aug. 10, 2008, Nature Neuroscience, online
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