Summary: AgRP neurons in the hypothalamus control the release of endogenous lysophospholipids, which helps control the excitability of neurons in the cerebral cortex and stimulate food craving.
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 neurons in the hypothalamus (the so-called AgRP, agouti-associated peptide neurons) control the release of endogenous lysophospholipids, which in turn control the excitability of neurons in the cerebral cortex, stimulating food intake.
In this process, a critical step of the signaling pathway is controlled by the enzyme autotaxin, which is responsible for the production of lysophosphatidyl acid (LPA) in the brain as a modulator of network activity.
Administration of ototaxin inhibitors can significantly reduce post-fasting and obese excessive food intake in animal models.
The article ‘AgRP neurons controlling food eating behavior in cortical synapses via peripherally derived lysophospholipids’ has now appeared in nature metabolism.
Eating disorders and especially obesity are among the most common causes of a variety of diseases in industrial societies worldwide, especially cardiovascular disease with permanent disabilities or fatal outcomes such as heart attacks, diabetes or strokes.
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 medication have so far proven ineffective.
A new treatment that modifies the excitability of the networks that control eating behavior will be a critical step toward controlling this widespread obesity.
The research team found an increased rate of obesity and associated type 2 diabetes in people with impaired LPA synaptic signaling.
A group led by Professor Johannes Vogt (Faculty of Medicine, University of Cologne), Professor Robert Nietsch (Medical School, University of Münster) and Professor Thomas Horvath (Yale University School of Medicine, New Haven, USA) has now shown that controlling the play of neuronal excitability in The cerebral cortex by LPA plays an essential role in controlling eating behaviour: 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) to LPA, which is active at the synapse. Synaptic LPA signals stimulate specific networks in the brain, resulting in increased food intake.
In the mouse model, after a period of fasting, increased serum LPC increased LPA stimulation in the brain. These mice exhibited typical foraging behavior. Both can be normalized by the administration of an otaxin inhibitor. On the other hand, obese mice lost weight when these inhibitors were taken continuously.
Johannes Vogt explained: “We saw a significant reduction in excessive food intake and obesity through genetic mutations and pharmacological inhibition of ATX. Our primary findings on LPA-controlled brain excitability, which we have been working on for years, also play a key role in eating behaviour.
Robert Nietsch sees the findings as an important step toward developing a new drug: “The data show that people with a disturbed synaptic LPA signaling pathway are more likely to be overweight and have type 2 diabetes. This is a strong indication of the potential therapeutic success of ATX inhibitors, which we are currently developing with the Hans Knöll Institute in Jena for use in humans.
These findings regarding the control of excitability of neural networks in eating behavior through lysophospholipids and the new therapeutic possibilities they suggest could contribute in the future to not only the treatment of eating disorders, but also neuropsychiatric diseases.
About this research in Neuroscience News
author: Eva Schisler
source: University of Cologne
Contact: Eva Schisler – University of Cologne
picture: The image is attributed to Johannes Vogt
original search: Access closed.
“AgRP neurons control feeding behavior at cortical synapses via peripheral derived lysophospholipidsBy Johannes Vogt. nature metabolism
AgRP neurons control feeding behavior at cortical synapses via peripheral derived lysophospholipids
Phospholipid levels are affected by peripheral metabolism. Within the central nervous system, synaptic phospholipids regulate glutamate 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 blood and cerebrospinal fluid rise after overnight fasting and lead to increased cortical excitability. Cortical excitation associated with LPA increases fasting-induced hypereating, and decreases after inhibition of LPA synthesis.
Mice that express a human mutation (Prg-1 . programR346T) leading to increased display of cortical excitability mediated by synaptic fat, 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 demonstrate that the effects of LPA after fasting are under the control of hypothalamic-associated peptide neurons (AgRP). Fasting-induced depletion of AgRP-expressing cells in adult mice reduces circulating LPAs, as well as cortical excitability, while limiting overeating.
These results reveal a direct effect of LPAs circulating under the control of AgRP neurons on cortical excitability, revealing an alternative non-neuronal pathway through which the hypothalamus can exert a strong influence on the cortex and thus influence food intake.
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