Identified signaling pathway controlling food intake
It has now been possible to develop a completely new approach to the treatment of eating disorders. The administration of so-called autotaxin inhibitors can prevent overeating, lose weight and reduce existing obesity.
In a new study involving experts from the University of Cologne
demonstrated a direct influence of so-called lysophosphatidic acid (LPA) on the excitability of nerve cells in the cerebral cortex, which stimulates food intake. The results of the study were published in the English-language journal "Nature Metabolism".
Overweight and obesity in Germany
Eating disorders and obesity are widespread in industrialized societies and cause many diseases. In 2021, 67% of men and 53% of women in Germany were overweight and 23% of adults were even obese, the researchers report, citing figures from the Robert Koch Institute (RKI).
Previous attempts to influence eating behavior with drugs have been ineffective. But developing a new therapy that modulates the excitability of networks that control eating behavior could hold the key to reducing obesity, the team say.
Effects of lysophospholipids on food intake
In the current study, it became clear that a group of nerve cells in the hypothalamus, known as agouti-related peptide neurons (AgRP), controls the release of endogenous lysophospholipids.
The researchers report that lysophospholipids, in turn, are responsible for controlling the excitability of nerve cells in the cerebral cortex that influence food intake.
What role does the enzyme autotaxin play?
In the process identified, the decisive step of the signaling pathway is controlled by the enzyme autotaxin. The team explains that this is responsible for the production of lysophosphatidic acid (LPA) in the brain as a modulator of network activity.
This regulation of the excitability of neurons in the cerebral cortex by LPA in turn plays an important role in controlling eating behavior and people with impaired LPA synaptic signaling are more likely to be affected by obesity and type 2 diabetes.
Autotaxin inhibitors prevent overeating
Experts also found that administration of autotaxin inhibitors significantly reduced post-fasting overeating – at least in animal models.
How is autotaxin converted to LPA?
AgRP neurons regulate the amount of lysophosphatidylcholine (LPC) in the blood. LPC reaches the brain by active transport. There it is converted to LPA by an enzyme called autotaxin (ATX), which is active at the synapse, the team explains.
LPA synaptic signals stimulate special networks in the brain, which are associated with increased food intake, experts continue to report.
The study showed that an increase in LPC in the blood after a period of fasting in mice leads to an increase in stimulating LPA in the brain. These animals showed typical behavior in their search for food.
Weight loss due to autotaxin inhibitors
If mice were given so-called autotaxin inhibitors, levels of LPC in the blood and levels of stimulating LPA in the brain normalized. When the inhibitors were given continuously, it was associated with decreased weight, the team said.
"Thanks to the genetic mutation and the pharmacological inhibition of ATX, we were able to determine a significant reduction in excessive food intake and obesity," reports the study's author, Professor Dr. Johannes Vogt in a press release from the University of Cologne.
“Our fundamental findings on PLA-controlled brain excitability, which we have been working on for years, also play a central role in eating behavior,” explains the expert. Author of the study, Professor Dr. Robert Nitsch adds that the knowledge acquired constitutes an important step in the development of new drugs.
ATX inhibitors already in development
"The data show that people with an impaired synaptic signaling pathway for APL are more likely to be obese and to have type 2 diabetes. This is a strong indication of the possible therapeutic success of inhibitors of ATX, which we are currently developing with the Hans Knöll Institute in Jena for use in humans,” adds Nitsch.
The researchers conclude that the improved understanding of the control of neural network excitation in eating behavior by lysophospholipids and the resulting new intervention options may contribute to the treatment of eating disorders in the future. (as)
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Sources:Heiko Endle, Guilherme Horta, Bernardo Stutz, Muthuraman Muthuraman, Irmgard Tegeder, et al. : AgRP neurons control feeding behavior at cortical synapses via peripherally derived lysophospholipids; in: Nature Metabolism (published June 27, 2022), Nature MetabolismUniversity of Cologne: Farewell to binge eating: Signaling pathway in the brain to control food intake decoded (published June 28, 2022), University of Cologne
This article contains general advice only and should not be used for self-diagnosis or treatment. It cannot substitute a visit to the doctor.