Cerebellum Plays Role in Stimulating Appetite in PWS, Study Discovers
MRI brain scans of Prader-Willi syndrome (PWS) patients unexpectedly revealed nerve cells in the cerebellum of the brain activated by food cues that promote appetite, a study demonstrated.
The findings suggest that the cerebellum may be a potential target for treating obesity in people with PWS.
The study, “Reverse-translational identification of a cerebellar satiation network,” was published in the journal Nature.
PWS is caused by the loss of or defects in paternal genes known to control metabolism, growth, appetite, intellectual skills, social behavior, and sleep. Excessive appetite (hyperphagia) and overeating, leading to obesity, are hallmarks of PWS.
Humans, as animals, have brain systems to ensure sufficient food intake. At the same time, some mechanisms limit food intake to help maintain a stable body weight. These processes are governed by internal sensors that balance the motivation to eat with the need to avoid overeating.
Treatments designed to control weight gain by targeting brain regions known to suppress food intake often fail at maintaining lasting weight loss, which suggests there are unidentified brains areas that regulate food intake. A further understanding of these mechanisms may support the development of more effective treatments for obesity.
A team led by researchers based at the University of Pennsylvania wondered if individuals with PWS exhibit differences in brain activity in regions that control eating.
To find out, 14 PWS patients (12 female, two male), with a mean age of 24.3, underwent whole-brain functional MRI scans, which measures brain activity by detecting changes in blood flow. As a control group, 14 people with simple obesity were included matched by age, sex, handedness (all right-handed), and body mass index (body fat content).
All participants were not taking growth hormone treatment or using appetite suppressants, and none had a history of neurological illness. Both scans were performed on the same day, one after fasting for at least four hours and the other within 15 minutes after eating a small standardized meal.
Analysis revealed that the only brain region with significant differences in nerve cell (neuron) activity between individuals with PWS and controls was deep inside the cerebellum — the structure located at the base and back of the brain.
The cerebellum is known to play an essential role in motor control, but it may also be involved in some cognitive functions, including attention and language, as well as emotions such as fear and pleasure responses.
“Our data suggest that a lack of cerebellar engagement in response to food cues may result in extreme hyperphagia,” the researchers wrote.
To pinpoint the precise location within the cerebellum activated by food intake, the team examined gene activity in the brains of mice. The experiments demonstrated that nerve cells called deep cerebellar nuclei (DCN) neurons — in an area known as the lateral (Lat) nucleus within the center of the cerebellum — were activated by food consumption.
Next, DCN neuron activity was manipulated, and food consumption monitored. Only the neurons in the front of the Lat region, called anterior DCNs (aDCN-LAT), lessened food intake. This activity was shown to reduce meal size and duration (satiation), but not the frequency or rate of eating, “suggesting that aDCN-LAT neuron activity terminates meals,” the team wrote.
Additional DCN activation experiments showed the lesser food intake was calorie-dependent, “further supporting the notion that this region is specifically tuned to energy status,” the scientists wrote. Further, mice with aDCN activation increased the volume of food consumption when the caloric density was decreased.
“Together, these results indicate that the activity in aDCN neurons diminishes food intake regardless of hunger state, palatability or caloric density without compensatory changes in energy expenditure,” the researchers noted.
A more detailed molecular examination of the DCNs in the Lat nucleus showed that, following re-feeding, immediate-early gene expression (activity) was increased in neurons that produce glutamate, one of the most common nervous system signaling molecules (neurotransmitters). These neurons are known as glutamatergic neurons.
Differences in gene expression within DCNs identified two classes of glutamatergic neurons, called class I and class II. Selective activation of class I glutamatergic neurons in the aDCN reduced food intake, similar to the entire aDCN, whereas activation of class II glutamatergic neurons did not change food intake.
“Thus, class I glutamatergic neurons in the aDCN-LAT are an important node acting downstream of satiation signals, because these neurons are both activated by nutritive signals and capable of suppressing food intake,” the researchers wrote.
Finally, they investigated whether the cerebellum interacts with food intake networks based on need, found in the brain region known as the hypothalamus, or with food intake networks based on reward, controlled by the neurotransmitter dopamine.
Activating an area within the hypothalamus containing hunger-sensitive neurons expressing the protein AgRP robustly increased food intake. In contrast, simultaneous activation of aDCN and AgRP neurons blocked this increase, “demonstrating that aDCN neurons are capable of overriding hypothalamic control of food intake,” the team noted.
Food rewards activate neurons in the brain’s ventral tegmental area (VTA), which triggers dopamine release into the ventral striatum brain region.
The activation of aDCN-LAT neurons led to a sustained release of dopamine in the ventral striatum, and there was a strong correlation between the levels of dopamine and a reduction in food intake. This result was mirrored by activating VTA neurons (and higher striatal dopamine levels), which led to greater reductions in food intake.
By blocking VTA neurons, thus reducing dopamine release in striatal neurons, aDCN-LAT stimulation restored dopamine to normal baseline levels. Notably, blocking VTA neuron activity during ongoing aDCN-LAT stimulation also completely restored food intake reductions caused by aDCN-LAT activation alone.
In addition, the rescue of food intake correlated with low levels of dopamine in the striatum brain region, “suggesting that the ability of aDCN-LAT neurons to reduce food intake occurs via an increase in VTA-[dopamine] neuron activity,” the researchers wrote.
“This modulation of DA signalling provides a powerful means for cerebellar output pathways to adaptively regulate food intake, and provides a potential target for pharmacological or deep-brain stimulation treatment of hyperphagia,” they added.
“Here, we report the unexpected finding that cerebellar output neurons are activated by food cues to promote satiation and highlight the cerebellum as a potential therapeutic node for conditions such as obesity and PWS,” the team concluded, adding that “cerebellar activity serves as a ‘brake’ to reduce meal size and food intake.”
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