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No more binge eating: Brain signaling pathway that controls food intake discovered – Neuroscience News

Overview: AgRP neurons in the hypothalamus regulate the release of endogenous lysophospholipids, help control cortical neuron excitability, and stimulate food cravings.

Source: University of Cologne

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

The scientists showed that a group of nerve cells in the hypothalamus (called AgRP, agouti-related peptide neurons) regulate the release of endogenous lysophospholipids, which in turn regulate the excitability of nerve cells in the cerebral cortex, which stimulates food intake.

In this process, the critical 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 thereby significantly reduce both excessive food intake after fasting and obesity in animal models.

The article ‘AgRP neurons regulate 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 a variety of diseases in industrialized societies around the world, especially cardiovascular diseases with permanent disabilities or fatal consequences such as heart attacks, diabetes or stroke.

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 seriously overweight (obese). Attempts to influence eating behavior with drugs have so far proved ineffective.

A new therapy that modulates the excitability 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 associated type II diabetes in people with impaired synaptic LPA signalling.

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) has now shown that the control of the excitability of neurons in the cerebral cortex by LPA plays an essential role in the control of eating behavior: AgRP neurons regulate the amount of lysophosphatidylcholine (LPC) in the blood.

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

In the mouse model, an increase in LPC in the blood after a period of fasting led to an increase in the stimulation of LPA in the brain. These mice showed typical food-seeking behavior. Both can be normalized by administering autotaxin inhibitors. In contrast, obese mice lost weight when these inhibitors were administered continuously.

Nerve cells from a mouse brain (green) and the protein PRG-1 (red). If the nerve cells contain PRG-1, the cells will appear in yellow. Credit: Johannes Vogt

Johannes Vogt explains: ‘We saw a significant reduction in excessive food intake and obesity through gene mutation and pharmacological inhibition of ATX. Our fundamental findings on the LPA-controlled excitability of the brain, which we have been working on for years, therefore also play a central role in eating behaviour.’

Robert Nitsch sees the findings as an important step towards the development of new drugs: ‘The data show 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 ATX inhibitors, which we are currently developing for use in humans together with the Hans Knöll Institute in Jena.’

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

About this neuroscience research news

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

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Original research: Closed access.
AgRP neurons regulate feeding behavior at cortical synapses via peripherally derived lysophospholipidsby Johannes Vogt. Nature Metabolism


Abstract

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

Phospholipid levels are affected 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 an overnight fast and lead to higher cortical excitability. LPA-related cortical excitability increases fasting-induced hyperphagia and decreases upon inhibition of LPA synthesis.

Mice expressing a human mutation (prg-1R346T) leading to higher synaptic lipid-mediated cortical excitability, increased fasting-induced hyperphagia. Accordingly, people with this mutation have a higher body mass index and a higher prevalence of type 2 diabetes.

We further show that the effects of fasting LPA are controlled by hypothalamic agouti-related peptide (AgRP) neurons. Depletion of AgRP-expressing cells in adult mice reduces fasting-induced elevation of circulating LPAs, as well as cortical excitability, while blunting hyperphagia.

These findings reveal a direct influence of circulating LPAs under control of hypothalamic AgRP neurons on cortical excitability, unmasking an alternative non-neuronal pathway that allows the hypothalamus to exert a robust impact on the cortex and thereby influence food intake.

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