Donuts. Candy bars. Cinnamon rolls. These sweet treats are hardly necessary for survival, but, for many of us, they’re difficult to resist—even when we’re not hungry.
Now, scientists have found that neurons in the part of the brain that control the fear response may also be responsible for the tendency to overeat fatty, sugary foods. In a study published Oct. 20 in Nature Neuroscience, a team led by researchers from Cold Spring Harbor Laboratory in Laurel Harbor, New York, described how they discovered that activating neurotensin neurons in the amygdala can regulate food preferences, feeding behavior and metabolic health. Their findings could eventually form the basis for future weight loss therapies.
Previous studies showed that many elements contribute to one’s ability to gain or lose weight. One theory that gained attention in recent years is the notion of a metabolic “set point,” a genetically determined weight that the body will return to regardless of how much or little an individual eats or exercises. However, most research on the brain networks behind this phenomenon focused exclusively on feeding behaviors, as opposed to the circuitry involved in deciding what to eat and how the body adapts to those decisions.
The Cold Spring Harbor team hoped to fill in this gap. They started by looking at a structure within the amygdala called IPAC for short, or interstitial nucleus of the posterior limb of the anterior commissure. Neurons in this region express neurotensin, a hormone that was previously implicated in reward pathway signaling and is activated by stimulation of taste cells.
After confirming that IPAC neurons express neurotensin, the scientists tested how the cells responded to a “healthy” versus an “unhealthy” diet. They fed either regular chow or high-fat chow to two separate groups of mice, both of which had been previously restricted from eating. The researchers found that neurotensin-expressing IPAC neurons were activated in the mice who received the high-fat chow but not in those who ate regular chow, indicating that consuming palatable food specifically stimulated the cells.
Based on this finding, they reasoned that IPAC neurotensin neurons could influence food preference more broadly by encoding what foods the mice found palatable. A series of feeding experiments showed not only that the cells were activated as the mice grew to prefer high-fat chow over standard chow but also that in individual mice, the neurons' activation was more robust when the high-fat chow came in the mouse's preferred flavor.
Next, the scientists sought to establish whether activating IPAC neurotensin neurons would lead the mice to overeat. They found that stimulating the cells led the mice to eat more food of all kinds—but especially high-fat chow in a preferred flavor—regardless of whether their food intake had been restricted, if they were fed or if they were overfed. The researchers were also able to condition the mice to prefer one flavor over another by stimulating the cells.
The researchers then conducted a series of experiments to find out if inhibiting or inactivating neurotensin neurons in the IPAC would change the mice’s feeding behavior, preferences and metabolism. They learned that inhibiting the cells in fed mice, then offering them high-fat chow, kept them from overeating. They also found that inactivating the cells prevented the mice from forming a preference for a more palatable diet.
Additional work revealed that the IPAC neurotensin neurons formed a network with cells in the lateral hypothalamus, which is involved in regulating food intake, food preference and energy expenditure. Activating neurons along the pathway between the IPAC and the lateral hypothalamus led the mice to exhibit the same overfeeding behaviors and diet preferences as earlier experiments.
Taken together, the data suggest that sensory stimulation of the neurotensin neurons in the IPAC, coupled with the cells’ projection to the lateral hypothalamus, results in a preference for high-fat foods and overeating.
“From a therapeutic point of view, these findings are highly relevant as they show that blocking a handful of … neurons leads to long-term weight loss, has beneficial effects on metabolic function and protects from obesity and metabolic syndromes,” the scientists wrote in their paper.
The scientists are now looking for ways to manipulate the cells so they can regulate overeating. They’re working on mapping out how the neurons respond to different types of foods.