Appetite brake discovered in the cerebellum – newly discovered circuit sends stop signal for food intake –

Surprising find: In our cerebellum, researchers have discovered a previously unknown regulator for our appetite. The circuit sends a signal that indicates satiety and stops eating. The exciting thing about it: This cerebellar signal drowns out even hunger signals from other appetite centers in the brain and also works with a diet. These neurons could thus offer a new therapeutic approach for people with poor appetite control.

The interplay between hunger and satiety is based on a complex interplay of various organs, hormones and neural circuits. Sensors query the blood sugar level and energy status and activate, among other things, the appetite center in the hypothalamus and other areas of the brain. These control our feeling of hunger, but also react to signals from the intestines and bile, which indicate fullness and calorie supply.

The problem, however: So far, therapies that address these actors in our appetite regulation have produced rather disappointing results. Certain active ingredients can curb the appetite and induce a feeling of satiety. Most of the time, however, they have significant side effects or their effects do not last long – for example, because our brain adapts. “Active substances that attach to the hypothalamus or the back of the brain are obviously not good helpers against obesity,” says senior author Nicholas Betley of the University of Pennsylvania.

Unexpected find in the cerebellum

But now Betley and his team have discovered a whole new player in the ensemble of appetite controllers. For their study, they used functional magnetic resonance imaging (fMRI) to examine how the brains of patients with Prader-Willi syndrome react to food stimuli. In this disease, a genetic defect triggers insatiable hunger without a feeling of satiety. Betley, first author Aloysius Low, and her colleagues compared the brain activity of these patients with that of healthy controls.

The result: As expected, there were differences – but surprisingly in none of the already known appetite centers. The only brain region that reacted significantly weaker in the Prader-Willi patients was instead the cerebellum. “The cerebellum literally stood out – and we all wondered, can this be real?” Says Betley.

To answer this question, the scientists carried out additional experiments with mice. In these, they either stimulated or inhibited different parts of the cerebellum and observed how this affected the feeding behavior of the animals.

The nuclei in the mouse cerebellum, which act as an appetite suppressant, are colored orange. © Betley Laboratory

Activation drastically reduces food intake

And indeed: if a certain group of neurons in the cerebellum was inhibited, the mice began to eat much more than normal. Conversely, stimulating these cerebellar nuclei resulted in the mice consuming 50 to 75 percent less food – regardless of whether they had previously fasted or not. “It was so amazing that at first I thought something was wrong,” says Betley.

But further tests confirmed the effect: if the anterior cerebellar nuclei were activated, the mice stopped eating sooner. The frequency of their meals did not change as a result, but the amount of food consumed at each meal did. Although the animals ate less than normal as a result, the compensatory overeating, which is typical for diets, did not occur, as the researchers observed.

Also interesting: the appetite-suppressing effect was independent of whether the mice were given high-calorie food with a lot of fat or sugar or rather low-calorie sparing food. “The animals with the cerebellar activation then adjusted the volume of the food they consumed so that they always consumed the same amount of calories,” report Betley and his team. That speaks in favor of this control mechanism

Appetite suppressor drowns out even hunger signals

These results show that there is a previously undetected center of appetite regulation in the cerebellum, as the researchers explain. According to their analyzes, this reacts to signals from the digestive tract: If enough nutrients have been absorbed, sensors in the intestine report this to the cerebellum nuclei via the vagus nerve and the rear brain and activate them. This triggers a feeling of satiety, which stops food intake.

“The activity of these neurons in the cerebellum acts as a brake on food intake and the size of meals,” explain Betley and his team. This brake in the cerebellum is apparently so strong that it drowns out even contrary signals from the hypothalamus: if the hunger neurons in mice were activated at the same time as the cerebellar nuclei, the animals still ate significantly less than normal.

Opportunity for new therapies

According to the researchers, the discovery of the cerebellar appetite brake not only provides new insights into the complex control mechanisms of our appetite regulation, it could also offer new starting points for therapies. For example, one could test whether the stimulation of the cerebellum works against overeating via magnetic coils attached to the outside of the head or light electric fields. (Nature, 2021; doi: 10.1038 / s41586-021-04143-5)

Those: University of Pennsylvania

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