Got food? A select group of neurons in the brain tells the body to eat more and conserve energy by releasing a common neurotransmitter, researchers report. Mice unable to release GABA from the select neurons were lean and resistant to diet-induced obesity.
The findings show the power of a new approach to exploring the specific functions of common neuro-transmitters in defined neurons, said senior author Bradford Lowell, HMS professor of medicine at Beth Israel Deaconess Medical Center.
The neurons in this study are known in scientific shorthand as AgRP, which might as well stand for “Accelerated gorging Results in Plumpness.” AgRP neurons are a key part of the brain circuitry in the hypothalamus that monitors the body’s energy balance and controls eating and metabolic rate. Too much of the neurons’ namesake AgRP protein makes mice obese, others have shown. Too little AgRP seems to keep mice lean as they age. And loss of the neurons in adult mice can lead to starvation.
Yet scientists have suspected other factors released by AgRP neurons also cast swing votes toward obesity or leanness. This study, published online Aug. 10 in Nature Neuroscience, verifies the importance of GABA release from AgRP neurons in regulating energy balance, said postdoctoral fellow Qingchun Tong, first author of the study. In further experiments, an extra shot of ghrelin, an appetite-stimulating hormone from the gut, triggered only half the additional eating in the selectively GABA-deficient mice compared to normal mice.
This is the second proof-of--concept paper for a new approach to pin down the action of broadly active neurotransmitters in specific neurocircuitry. By combining several genetic tricks, Tong and his colleagues created two categories of mice. One group, called menu A, carries genetic tags to turn on the Cre enzyme in selected neurons. The other mice, menu B, have specific lox-labeled genes, which Cre targets. Breeding a mouse from menu A with one from menu B can produce mice with a specific deletion of lox-labeled genes in regions where the Cre enzyme is expressed.
For this paper, Tong crossed a mouse from each menu—in this case, one that expressed Cre recombinase in AgRP neurons and another with a lox target to eliminate the protein that transports the inhibitory GABA into vesicles. Without GABA accumulation in vesicles, synapses fire blanks instead of neurotransmitters. For a paper in the May 2007 Cell Metabolism, Tong and his colleagues used the same method to create and study mice deficient in releasing glutamate from ventromedial hypothalamic (VMH) neurons and found that the excitatory neurotransmitter in those neurons helps prevent hypoglycemia. Many of the mice on each menu are available from Jackson Laboratory to other researchers.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: National Institutes of Health; the Beth Israel Deaconess Medical Center Transgenic Facility, which is supported by the Boston Obesity Nutrition Research Center and the Boston Area Diabetes Endocrinology Research Center; National Institutes of Health-funded Boston Obesity Nutrition Research Center; and the North American Association for the Study of Obesity
