No more binge eating: Signal pathway in brain that controls food intake discovered – Neuroscience News

Summary: AgRP neurons in the hypothalamus control the release of endogenous lysophospholipids, helping to control the excitability of neurons in the cerebral cortex and stimulating the desire for food intake.

Source: University of Cologne

A group of researchers has developed an entirely new approach to treating eating disorders.

Scientists have shown that a group of nerve cells in the hypothalamus (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, the crucial step of 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 administration of autotaxin inhibitors can thus 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” now appears in Natural metabolism.

Eating disorders and in particular obesity are one of the most common causes of various diseases in industrialized societies around the world, especially cardiovascular diseases leading to permanent disabilities or fatal outcomes such as heart attacks , diabetes or stroke.

The Robert Koch Institute reported in 2021 that 67% of men and 53% of women in Germany were overweight. 23 percent of adults are severely overweight (obese). Attempts to influence eating behavior with drugs have so far proven ineffective.

A new therapy modulating the excitability of the networks that control eating behavior would be a decisive step towards controlling this generalized obesity.

The research team found an increased rate of obesity and type II diabetes in people with impaired APL synaptic signaling.

A group led by Professor Johannes Vogt (Faculty of Medicine, University of Cologne), Professor Robert Nitsch (Faculty of Medicine, University of Münster) and Professor Thomas Horvath (Yale School of Medicine, New Haven, USA) comes to show that the control of the excitability of the neurons of the cerebral cortex by the LPA plays an essential role in the control of eating behavior: the AgRP neurons regulate the quantity of lysophosphatidylcholine (LPC) in the blood.

By active transport, LPC reaches the brain, where it is converted by the enzyme autotaxin (ATX) into LPA, which is active at the synapse. LPA synaptic signals stimulate specific networks in the brain, leading to increased food intake.

In the mouse model, after a period of fasting, an increase in LPC in the blood resulted in an increase in stimulatory LPA in the brain. These mice showed typical foraging behavior. Both could be normalized by administering autotaxin inhibitors. Obese mice, on the other hand, lost weight when these inhibitors were continuously administered.

Nerve cells from a mouse brain (green) and the PRG-1 protein (red). If the nerve cells contain PRG-1, the cells appear yellow. 1 credit

Johannes Vogt explained: “We found a significant reduction in excessive food intake and obesity due to genetic mutation and pharmacological inhibition of ATX. Our fundamental findings on PLA-controlled brain excitability, which we have been working on for years, therefore also play a central role for eating behavior.

Robert Nitsch sees the results as an important step towards the development of new drugs: “The data shows that people with a disrupted synaptic LPA signaling pathway are more likely to be overweight and have type II diabetes. This is a strong indication of a possible therapeutic success of the ATX inhibitors, which we are currently developing with the Hans Knöll Institute in Jena for use in humans.

These findings on the control of neural network excitation in eating behavior by lysophospholipids and the new therapeutic possibilities they suggest may in the future contribute not only to the treatment of eating disorders, but also neurological and psychiatric diseases.

About this neuroscience research news

Author: Eva Schisler
Source: University of Cologne
Contact: Eva Schissler – University of Cologne
Image: The image is credited to Johannes Vogt

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Original research: Access closed.
“AgRP Neurons Control Feeding Behavior at Cortical Synapses Via Peripherally-Derived Lysophospholipids” by Johannes Vogt. Natural metabolism


Summary

AgRP neurons control feeding behavior at cortical synapses via peripherally derived lysophospholipids

Phospholipid levels are influenced by peripheral metabolism. Within the central nervous system, synaptic phospholipids regulate glutamatergic transmission and cortical excitability. It is unknown whether changes in peripheral metabolism affect brain lipid levels and cortical excitability.

Here, we show that lysophosphatidic acid (LPA) species levels in blood and cerebrospinal fluid are elevated after overnight fasting and lead to higher cortical excitability. LPA-related cortical excitability increases in fasting-induced hyperphagia and decreases after inhibition of LPA synthesis.

Mouse expressing a human mutation (Prg-1R346T) leading to increased synaptic lipid-mediated cortical excitability display increased fasting-induced hyperphagia. As a result, human subjects carrying this mutation have a higher body mass index and prevalence of type 2 diabetes.

We further show that the effects of LPA after 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 attenuating hyperphagia.

These results reveal a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability, unveiling an alternative non-neuronal pathway by which the hypothalamus can exert a robust impact on the cortex and thus affect food intake.

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