Published: 03.12.09
New molecular switch

Movement comes with appetite

A body that is provided with food too often gets caught up in the maelstrom of a lack of exercise, obesity and ultimately diabetes. The trigger is a molecular switch that is controlled by insulin, a new study by scientists from ETH Zurich has revealed.

Peter Rueegg / Claudia Naegeli

Eat breakfast like a king, lunch like a prince and dinner like a pauper. And noth-ing in between: no snacks, no sweets, not even anything we think of as healthy. For in order to stay healthy the body needs to fast between meals. At least this is what nutritionists would recommend were they to translate the results of a new study from ETH Zurich into practical terms. After all, the research group headed by Markus Stoffel, a professor from the Institute of Molecular Systems Biology at ETH Zurich, has discovered an important molecular mechanism that underlies a lack of exercise and therefore obesity. The researchers present their findings in the current issue of the journal Nature.

Hunger makes you active

The key switch player in this is a transcription factor called Foxa2. Transcription factors are proteins that make sure other genes are activated and converted into proteins. Foxa2 is found in the liver, where it influences fat-burning, but also in two important neuron populations in the hypothalamus – the region of the brain that controls the daily rhythm, sleep, intake of food and sexual behavior. The control element for Foxa2 activity is insulin, in both the liver and the hypothalamus.

If a person or animal ingests food, the beta cells in the pancreas release insulin, which blocks Foxa2. When fasting, there is a lack of insulin and Foxa2 is active. In the brain, the scientists have discovered, Foxa2 assists the formation of two proteins: MCH and orexin. These two brain messenger substances trigger dif-ferent behavior patterns: the intake of food and spontaneous movement. If mammals are hungry, they are more alert and physically active. In short, they hunt and look for food. “If you watch a cat or a dog before feeding it, you can see this very clearly”, says Stoffel.

Explanation found for lack of movement

The researchers discovered a disorder in obese mice: in these animals, Foxa2 is permanently active, regardless of whether the animals are fasting or full. This explains a well-known but until now unaccountable phenomenon: the lack of movement in obese people and animals.

To prove this, the researchers used a genetic trick to breed mice, in the brains of which Foxa2 is always active, regardless of whether they have just eaten or are fasting. These mice produce more MCH and orexin and move five times more than normal animals, in which insulin deactivates Foxa2 after eating or which are obese. The genetically modified mice lose fatty tissue and form larger muscles. Their sugar and fat metabolism works flat out and their blood values are considerably improved.

Three meals a day suffice

For Stoffel, the study clearly shows that, “The body needs fasting periods to stay healthy.” Moreover, you should make sure you have a good body weight. He therefore doesn’t think much of eating many little meals spread out over the day; it is better to eat less frequently but well, and leave room in between to get hun-gry. After all, because insulin is released during every meal, thus suppressing Foxa2, the motivation to do physical exercise and burn sugar and fat visibly de-creases.

Reference

Silva JP, von Meyenn F, Howell J, Thorens B, Wolfrum C, Stoffel M. Regulation of adaptive behavior during fasting by hypothalamic Foxa2. Nature. Epub 2009 December 3, doi: 10.1038/nature08589.

 
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