The Brain’s Brake on Overeating

We all have that friend. The one who can eat donuts and ice cream–essentially whatever they want–without gaining weight. On the other extreme, some people seem to gain weight no matter how little they eat or how much they exercise. So, what exactly is it that allows one person to remain thin without much effort but requires another to struggle to avoid gaining weight?

On the most basic level, your weight depends on the number of calories you consume, store, and burn up, but each of these factors is influenced by a combination of your genes and environment. They can affect your physiology and behavior, ranging from how fast you burn calories to what types of food you choose to eat. The human body maintains a delicate balance of “adaptive feeding” to ensure sufficient food intake and limit its consumption to maintain a stable body weight. In the face of environmental changes and food availability, this balance ensures body weight homeostasis. Today, this equilibrium is greatly skewed to favor a positive energy balance. As a result, the increasing prevalence of obesity highlights the need to better understand body weight control.

A team of researchers, led by Dr. Albert Chen at the Scintillon Institute, Dr. Nicholas Betley, and Dr. Aloysius Low at the University of Pennsylvania, recently found that a distinct group of neurons in the cerebellum—a region of the brain that had previously never been linked to hunger—controls appetite. The project began with an unexpected finding by Chen’s team, who noticed that they could make mice eat less by activating a small group of neurons known as anterior deep cerebellar nuclei (aDCN) within the cerebellum. Despite their specialty in spinal and cerebellar circuits involved in motor control, Chen and Betley contacted their colleagues—Dr. Laura Holsen (Brigham and Women’s Hospital), Dr. Roscoe Brady (Beth Israel Deaconess Medical Center), and Dr. Mark Halko (McLean Hospital)—affiliated with Harvard Medical School to see whether this phenomenon could be observed in humans with eating disorders.

The Harvard scientists had previously collected a data set of functional magnetic resonance imaging (fMRI) of fourteen individuals with Prader-Willi syndrome (PWS), a rare genetic disorder characterized by insatiable hunger, developmental delay, and behavioral problems that can lead to life-threatening obesity. The researchers recorded the brain activity of these subjects while they viewed images of food either after eating a meal or after fasting for at least four hours. A new analysis of the data compared to the fMRI scans of unaffected individuals confirmed that the deep cerebellum was the only brain region that showed a significant difference in neural activity between PWS and control subjects. To precisely define the subgroup of neurons in the cerebellum responsible for this phenotype, Low, a Ph.D. graduate of Chen’s lab, transferred to Betley’s lab at the University of Pennsylvania, which specializes in studying homeostatic and hedonic feeding circuits. 

“It had always been a graduate school dream of mine to do a project together with Nick,” Chen said. “In fact, a lot of the collaborators on this project had worked together on the same floor in graduate school [at Columbia University], so we were determined to make this project work.” 

“It was through Low’s dedication, however, that we were able to see this collaboration through,” Betley said. “Every project for a graduate student runs into difficulty—Low had discovered an incredible feeding phenotype but could not get the phenotype independent of a reduction in locomotion.” While Low had observed that the specific activation of the aDCN in the cerebellum reduced food intake in mice, he also needed to prove that this phenotype was independent of locomotion, which was also known to be regulated in the cerebellum. Furthermore, since the cerebellum had never been linked to appetite regulation before, the proof had to be indisputable. For example, if the activation of the aDCN reduced the motor skills of the mice, which caused the subsequent decrease in food intake, they would not be able to definitively conclude that the aDCN was a direct feeding center. 

“We were close to killing the project so many times,” Chen said. “But, by continuing to pursue his theory and performing over a hundred new experiments, Low was able to define the precise subpopulation of neurons involved in regulating feeding—and that was the entire difference,” Betley said. Once Low had developed mice models where the feeding phenotype was completely isolated from locomotion, they could conclusively prove that the aDCN really was a feeding center rather than a center that affects feeding through a change in locomotion. 

Further experiments then elucidated the mechanism behind the feeding phenotype. The activation of aDCN activates ventral tegmental area dopamine neurons that release dopamine in the ventral striatum, a region of the brain involved in reward processing, motivation, and decision-making. The team had observed a strong correlation between levels of ventral striatal dopamine and reduction in food intake after aDCN activation. This seems paradoxical since higher dopamine levels should reinforce food intake while decreasing dopamine levels may result in anorexia. However, the long-lasting increase in baseline dopamine levels can reduce its responsiveness to food. Increasing baseline levels blunt how the brain’s pleasure center responds to food, similar to how the effects of drug intake are blunted over time. 

The team also observed that the reduction in food intake did not cause any metabolic compensation or increased food intake to make up for the missed meal. Caloric deficits in animals usually cause their metabolism to slow down, but this was not observed in the mice models with activated aDCN. Thus, these findings have great potential to address obesity, as a reproducible caloric deficit will ultimately result in weight loss.

Today, Chen and Betley continue their collaboration to test whether they can manipulate aDCN activity in patients with PWS using a noninvasive intervention known as transcranial magnetic stimulation (TMS). They are hopeful that TMS can be used to activate aDCN activity to reduce food intake in patients with PWS. These experiments could not only lead to a clinical trial to treat PWS but also open up new avenues for treating other types of eating disorders.

Chen and Betley hope that their research will change how scientists view neuroscience and how the general public views obesity more broadly. Their findings are only the latest in a series of discoveries revealing that different regions of the brain are not simply responsible for one specific subset of behaviors but rather overlap in their functions to regulate human behavior. Thus, Chen and Betley hope that large collaborations between experts in different brain regions will become more common. 

Moreover, they hope that these findings will change how we view individuals with obesity. Unfortunately, it is common to blame people with obesity for their condition. However, rather than blaming a person for their lack of control or willpower, we might be more sympathetic to their condition, understanding that obesity is a disease. As we continue to learn more about how our brain, genetics, and environment impact our bodies, we will become more equipped to address eating disorders in a more compassionate and constructive manner.