A new study reveals a signal pathway to control binge eating

The approach may result in a new way of dealing with eating disorders.
Loukia Papadopoulos
A man sitting and eating burgers.South_agency/iStock

A group of researchers from the University of Cologne has developed an entirely novel approach to treating eating disorders that may be the key to finally controlling such harmful impulses, according to a press release published by the institution on Thursday. 

The neurons that stimulate food intake

Using mouse models, the researchers showed 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 stimulate food intake.

The scientists further deduced that AgRP neurons located in the hypothalamus could trigger sensations of hunger when activated. In this research, AgRPs were also linked to an enzyme in the brain called autotaxin (ATX).

Through intensive study, the researchers found that by inhibiting ATX in mice, they could control food cravings in the animals.

A new study reveals a signal pathway to control binge eating
Nerve cells of a mouse brain (green) and the protein PRG-1 (red). If the nerve cells contain PRG-1, the cells appear in yellow. Credit: Johannes Vogt

"We saw a significant reduction in excessive food intake and obesity through gene mutation and pharmacological inhibition of ATX," said in the statement Johannes Vogt, a professor at the Faculty of Medicine at the University of Cologne in Germany.

In this process, the crucial step of the signaling pathway is controlled by the ATX, which is responsible for the production of lysophosphatidic acid (LPA) in the brain as a modulator of network activity. The researchers, therefore, concluded that the administration of autotaxin inhibitors could possibly significantly reduce both excessive food intake after fasting and obesity in animals.

"The data shows that people with a disturbed synaptic LPA signaling pathway are more likely to be overweight and suffer from type II diabetes. This is a strong indication of a possible therapeutic success of ATX inhibitors, which we are currently developing together with the Hans Knöll Institute in Jena for use in humans," said neuroscientist Robert Nitsch from the University of Münster in Germany.

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Promising results 

It's still early for the research but the first results delivered are indeed promising. This latest study could be an important first step in efforts to control eating disorders and obesity through the use of targeted drugs.

So far, any such efforts have largely failed. The new approach, however, shows promise for also helping in treating various neurological and psychiatric illnesses.

The researchers are now working on developing a series of ATX-blocking drugs for future testing on overweight individuals. And the researchers won't have to look very far to find test subjects.

The Robert Koch Institute reported in 2021 that 67 percent of men and 53 percent of women in Germany are overweight, with 23 percent of adults being severely overweight (obese). This is extremely problematic when considering that obesity can lead to many significant health conditions and can even interfere with the treatment of cancer.

Could this be the treatment we have been waiting for?

The study is published in the journal Nature.

Phospholipid levels are influenced by peripheral metabolism. Within the central nervous system, synaptic phospholipids regulate glutamatergic transmission and cortical excitability. Whether changes in peripheral metabolism affect brain lipid levels and cortical excitability remains unknown. Here, we show that levels of lysophosphatidic acid (LPA) species in the blood and cerebrospinal fluid are elevated after overnight fasting and lead to higher cortical excitability. LPA-related cortical excitability increases fasting-induced hyperphagia, and is decreased following inhibition of LPA synthesis. Mice expressing a human mutation (Prg-1R346T) leading to higher synaptic lipid-mediated cortical excitability display increased fasting-induced hyperphagia. Accordingly, human subjects with this mutation have higher body mass index and prevalence of type 2 diabetes. We further show that the effects of LPA following fasting are under the control of hypothalamic agouti-related peptide (AgRP) neurons. Depletion of AgRP-expressing cells in adult mice decreases fasting-induced elevation of circulating LPAs, as well as cortical excitability, while blunting hyperphagia. These findings reveal a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability, unmasking an alternative non-neuronal route by which the hypothalamus can exert a robust impact on the cortex and thereby affect food intake.

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