A group of researchers has developed a completely new approach to treating eating disorders. Scientists have shown that a group of nerve cells in the hypothalamus (so-called AgRP, agouti-related peptide neurons) control the release of endogenous lysophospholipids, which in turn control the excitability of nerve cells in the cerebral cortex, which stimulates food intake. In this process, a key step in the signaling pathway is controlled by the enzyme autotaxin, which is responsible for the production of lysophosphatidic acid (LPA) in the brain as a modulator of network activity. The use of autotaxin inhibitors in this way can significantly reduce both excessive food intake after fasting and obesity in animal models. The article ‘AgRP neurons control food intake behavior at cortical synapses via peripherally derived lysophospholipids’ has now appeared in Nature Metabolism.
Eating disorders, and especially obesity, are one of the most common causes of various diseases in industrialized societies around the world, especially cardiovascular diseases with permanent disability or fatal outcomes such as heart attacks, diabetes or strokes. The Robert Koch Institute reported in 2021 that 67 percent of men and 53 percent of women in Germany are overweight. 23 percent of adults are severely overweight (obese). Attempts to influence dietary behavior with drugs have so far proved ineffective. A new therapy that modulates the irritability of networks that control eating behavior would be a decisive step toward controlling this widespread obesity.
The research team found an increased rate of obesity and concomitant type II diabetes in people with impaired synaptic LPA signaling. A group led by Professor Johannes Vogt (University of Cologne School of Medicine), Professor Robert Nitsch (University of Münster School of Medicine) and Professor Thomas Horvath (Yale School of Medicine, New Haven, USA) has now shown that controlling the excitability of neurons in the cerebral cortex LPA plays an important role in controlling eating behavior: AgRP neurons regulate the amount of lysophosphatidylcholine (LPC) in the blood. By active transport, LPC reaches the brain, where the enzyme autotaxin (ATX) converts it to LPA, which is active at the synapse. Synaptic LPA signals stimulate specific networks in the brain, leading to increased food intake.
In a mouse model, after a period of starvation, an increase in LPC in the blood led to an increase in stimulatory LPA in the brain. These mice showed typical food-seeking behavior. Both can be normalized by the use of autotaxin inhibitors. Obese mice, on the other hand, lost weight when these inhibitors were administered continuously. Johannes Vogt explained: ‘We have seen a significant reduction in excessive food intake and obesity through gene mutations and pharmacological inhibition of ATX. Our fundamental findings on LPA-controlled brain irritability, which we have been working on for years, also play a central role in eating behavior. ‘ Robert Nitsch sees these findings as an important step toward the development of new drugs: ‘Data show that people with impaired LPA synaptic signaling pathways are more likely to be overweight and suffer from type II diabetes. This is a strong indicator of the possible therapeutic success of ATX inhibitors, which we are currently developing together with the Hans Knöll Institute in Jena for human use. ‘
These findings on the control of excitation of neural networks in dietary behavior through lysophospholipids and the new therapeutic possibilities they suggest could in the future contribute not only to the treatment of eating disorders, but also to neurological and psychiatric diseases.
Materials provided by the University of Cologne. Note: Content can be edited for style and length.