Being hungry is not fun. And when you're trying to lose weight, hunger is just begging you to shove whatever is on the break room table at work right in your piehole (hopefully, it's pie). What causes hunger and can we - dare we - stop it?

Harvard Medical School investigators at Beth Israel Deaconess Medical Center working with researchers at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health, published a study in Nature Neuroscience that a melanocortin 4 receptor-regulated (MC4R) circuit serves as the neural link that inhibits and controls eating. Their discovery shows that this brain circuit not only promotes fullness in hungry mice but also removes the almost painful sensation of grinding hunger, findings that could provide a promising new target for the development of weight-loss drugs.

"One reason that dieting is so difficult is because of the unpleasant sensation arising from a persistent hunger drive," explained the study's co-senior author Bradford Lowell, HMS professor of medicine at Beth Israel Deaconess, according to a press release. "Our results show that the artificial activation of this particular brain circuit is pleasurable and can reduce feeding in mice, essentially resulting in the same outcome as dieting but without the chronic feeling of hunger."

A key discovery are agouti-peptide-expressing (AgRP) neurons, a small group of neurons located in the brain's hypothalamus that detect caloric deficiency and drive intense feeding.

"When these AgRP neurons are 'turned on,' either by fasting or by artificial means, laboratory animals eat voraciously," said Lowell, according to the press release.

"Determining the identity of these 'satiety' neurons is the key to establishing the blueprint for how the brain can regulate appetite," added Lowell. "It was an important missing point of connection in the wiring diagram."

"There is a major hypothesis called 'drive reduction' that proposes that you eat to get rid of the unpleasant feeling of hunger," Lowell said, according to the press release. "This is in contrast to other views that propose that you eat because the taste of good food is rewarding. We, therefore, needed to conduct a behavioral experiment that would tell us whether this PVH MC4R → LPBN circuit, which mice normally activate by eating, would be pleasant if activated artificially, in the absence of any food being consumed."

To answer this question, co-senior author Michael Krashes and his colleagues at the NIDDK developed a behavioral experiment in which laser stimulation served as a surrogate for eating food. The experiment also enabled the mice to control the activation of their PVH MC4R → LPBN circuit based on their spatial location.

"We built a two-chamber apparatus separated by a doorway through which the hungry animals were free to move back and forth, as we tracked their activity," Krashes said, according to the press release. "If the animal moved into one chamber, computer software triggered the delivery of the blue laser light, which stimulated the animal's PVH MC4R → LPBN brain circuit. But when the animal returned to the other chamber, the laser switched off and the circuit was no longer stimulated."

The scientists followed the mice for 25 minutes to determine which chamber the animals preferred. "Normal mice displayed no preference for either chamber," said Krashes, "but the genetically engineered mice, which were able to stimulate the brain's PVH MC4R → LPBN circuit, greatly preferred the blue light-associated chamber, highlighting the gratifying sensation that took away their bad feelings of hunger."

Remarkably, Krashes said, when this experiment was repeated in mice that had recently eaten a meal, and therefore were not experiencing the negative feelings of hunger, turning on the satiety-promoting PVH MC4R → LPBN circuit lost its positive value, and the animals no longer showed a preference for the light-paired chamber.

"If the animals had found food in one particular chamber, then we expect that they would have stayed in that chamber and would have eaten, but since there was no food, they found another way of achieving the same result by self-stimulating the satiety-promoting PVH MC4R → LPBN circuit," Krashes explained.

"Turning on the PVH-MC4R satiety neurons had the same effect as dieting, but because it directly reduced the hunger drive it did not cause the gnawing feelings of discomfort that often come with dieting," said Lowell, according to the press release. "Our findings suggest that the therapeutic targeting of these cells may reduce both food consumption and the aversive sensations of hunger-and therefore may be an effective treatment for obesity."

This work was supported in part by the Boston Area Diabetes Endocrinology Research Center; the University of Edinburgh Chancellor's Fellowship; US National Institutes of Health grants R01DK096010, R01DK089044, R01DK071051, R01DK075632; R37DK053477, BNORC Transgenic Core P30DK046200, BADERC Transgenic Core P30DK057521, F32DK089710; K08DK0671561; R01DK088423 and R37DK0053301 and an American Diabetes Association Mentor-Based Fellowship. This research was also supported, in part, by the Intramural Research Program of the NIDDK, National Institutes of Health (1ZIADK075087, 1ZIADK075088).