Brain receptors for dopamine and insulin coordinate to control compulsive eating

A new study in mice reveals how receptors for dopamine and insulin act together in a specific brain region to regulate compulsive eating habits. The research, published in Molecular Psychiatry, highlights a cellular mechanism that stops animals from overconsuming sugary and fatty foods. These findings offer a biological explanation for why certain eating disorders and metabolic conditions frequently occur together.

Compulsive eating involves an intense drive to consume highly palatable foods regardless of negative health consequences. This behavior shares behavioral traits with substance addiction. Repeated overconsumption of foods high in fat and sugar can lead to obesity and metabolic diseases like diabetes.

Previous research linked both food cravings and metabolic disturbances to the reward pathways in the brain. Dopamine is a chemical messenger that helps the brain evaluate rewards and motivation. One specific docking station for this chemical, the dopamine D2 receptor, influences impulsivity and food addiction.

Another key component of metabolic health is insulin, a hormone that regulates blood sugar. The brain also contains insulin receptors, which help manage feeding behaviors. The precise relationship between these two receptor types during food consumption has remained largely unexplored.

The current research was led by Bokyeong Kim and Ja-Hyun Baik at Korea University, alongside a team of scientists from several South Korean institutions. The researchers focused on the central amygdala, a deep brain structure that processes emotions, motivation, and environmental cues. They noticed that dopamine D2 receptors and insulin receptors were often located on the exact same cells within this region.

The researchers first observed how a total lack of D2 receptors affects eating behavior. They used a small study of mice genetically engineered to lack these receptors entirely, comparing them to unaltered mice. Both groups were trained to press a lever to receive a sugary food pellet.

Once the animals learned this task, the researchers introduced a mild electric foot shock alongside the food reward. The unaltered mice stopped pressing the lever to avoid the punishment. The mice lacking D2 receptors kept pressing the active lever despite the shocks, exhibiting a compulsive drive for the sweet food.

To see if this effect was specific to the central amygdala, the team conducted a second experiment. They used targeted viral injections to remove D2 receptors only in the central amygdala of normal mice. When these mice faced the foot shock test, they also demonstrated heightened lever pressing for the sugary pellets.

Next, the team examined the relationship between dopamine and insulin receptors on these specific cells. They found that roughly 60 percent of the central amygdala neurons containing D2 receptors also carried insulin receptors. When the researchers removed the D2 receptors, the expression of insulin receptors in that brain region dropped by more than half.

The scientists then infused insulin or a dopamine-mimicking drug into the central amygdala of the mice. In unaltered mice, both chemicals triggered a process called phosphorylation, a chemical modification that activates the insulin receptors. In mice lacking D2 receptors, neither chemical activated the insulin receptors.

This demonstrated that dopamine receptors actively control insulin receptor function. The researchers traced this connection to a specific protein that normally inhibits insulin signaling. Activating the D2 receptors suppressed this inhibitory protein, which allowed the insulin receptors to function more freely.

To test if the insulin receptors themselves influence feeding, the researchers engineered a group of mice to lack insulin receptors exclusively on the neurons containing D2 receptors in the central amygdala. These mice were subjected to the lever-pressing task with foot shocks. Similar to the dopamine receptor mutants, these mice ignored the punishment and continued seeking the sweet food.

The researchers also examined the electrical properties of these brain cells using isolated brain tissue. They recorded the electrical activity of the central amygdala neurons in a controlled laboratory setting. Applying the dopamine-mimicking drug alone did not change the baseline electrical excitability of the cells.

However, when the researchers bathed the cells in a mixture of both insulin and the dopamine-mimicking drug, the neurons became highly electrically active. This indicated that the two types of receptors work together synergistically. The combined chemical signals drastically increased the electrical firing capacity of the specific brain cells.

The team then monitored the real-time activity of these specific brain cells in live animals. They used fiber photometry, a technique that employs tiny optic fibers to measure the calcium signals of active neurons. The researchers recorded the brain activity of mice while they consumed standard chow and while they ate a high-fat, high-sugar diet.

The activity of the central amygdala neurons containing D2 receptors decreased substantially when the mice ate the highly palatable food, while normal chow produced no change. Mice with lower neuron activity ate higher quantities of the rich food. When the researchers injected drugs to activate these receptors, the neuron activity stabilized, and the mice reduced their consumption of the sweet and fatty food.

To manipulate this circuit directly, the researchers utilized optogenetics. This method allows scientists to turn specific brain cells on or off using targeted flashes of light. In a small study of mice, they used light to silence the neurons containing D2 receptors in the central amygdala.

Silencing these cells caused the mice to eat vastly larger amounts of the sugary and fatty food. Conversely, using light to artificially activate these cells reduced the animals’ food intake.

However, there was a biological catch to this suppression. When the researchers blocked the insulin receptors with a chemical inhibitor, the light-induced activation of the D2 receptor-expressing neurons no longer stopped the mice from overeating. These neurons required functional insulin receptors to put the brakes on compulsive food consumption.

Finally, the scientists measured dopamine release in the central amygdala during extended access to the rich diet. Mice with reduced dopamine receptors in this region exhibited blunted dopamine release when they had constant access to the food. In a separate group given access to the rich food for only one hour a day, mice with reduced D2 receptors consumed roughly 64 percent of their daily calories during that hour, a binge-like eating pattern.

These experiments were conducted in mice, and animal models of feeding do not perfectly replicate human eating disorders or food addiction. The researchers used a lever-pressing task with foot shocks to model compulsivity, which measures the persistence of a habit despite physical punishment. This represents only one facet of human compulsive behavior, which involves complex emotional and psychological triggers.

Future studies will need to investigate exactly how this cellular machinery adapts over a longer lifespan. Researchers also hope to explore how these cells change after prolonged exposure to obesity-inducing diets. Understanding this receptor partnership might eventually guide new medical treatments that target both dopamine and insulin pathways to treat metabolic diseases and eating disorders simultaneously.

The study, “Dopamine D2 receptor modulation of insulin receptor signaling in the central amygdala: implications for compulsive-like eating behavior,” was authored by Bokyeong Kim, Minji Kim, Hyun-Yong Lee, Jung Hyun Pyo, Jihee Seo, Yoon Jeon, Ho Lee, Joung-Hun Kim, Seung Hyun Ahn, Sung Wook Chi, Je Kyung Seong, and Ja-Hyun Baik.