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Summary: AgRP neurons in the hypothalamus control the release of endogenous lysophospholipids, help control the excitability of cerebral cortex neurons, and stimulate food craving.
Source: University of Cologne
A group of researchers have developed a completely new approach to treating eating disorders.
The scientists showed that a group of neurons in the hypothalamus (called AgRPs, agouti-related peptide neurons) control the release of endogenous lysophospholipids, which in turn control the excitability of neurons in the cerebral cortex, which stimulates food intake.
The decisive 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 administration of autotaxin inhibitors can significantly reduce both excessive food intake after fasting and obesity in animal models.
The article “AgRP neurons regulate feeding behavior at cortical synapses via peripherally derived lysophospholipids” is now published in natural metabolism.
Eating disorders and in particular obesity are one of the most common causes of a large number of diseases in industrial societies worldwide, in particular cardiovascular diseases with permanent disabilities 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 eating behavior with medication have so far had no effect.
A novel therapy that modulates the excitability of networks that control eating behavior would be a critical step in controlling this widespread obesity.
The research team found an increased rate of obesity and associated type II diabetes in people with impaired synaptic LPA signaling.
A group led by Professor Johannes Vogt (Faculty of Medicine, University of Cologne), Professor Robert Nitsch (Faculty of Medicine, University of Munster) and Professor Thomas Horvath (Yale School of Medicine, New Haven, USA) has now shown that this is the case LPA excitability of neurons in the cerebral cortex plays an essential role in controlling eating behavior: AgRP neurons regulate the amount of lysophosphatidylcholine (LPC) in the blood.
Active transport takes LPC to the brain, where it is converted to LPA by the enzyme autotaxin (ATX), which is active at the synapse. Synaptic LPA signals stimulate certain networks in the brain, leading to increased food intake.
In the mouse model, after a period of fasting, an increase in blood LPC led to an increase in stimulatory brain LPA. These mice showed typical foraging behavior. Both could be normalized by administering autotaxin inhibitors. In contrast, obese mice lost weight when these inhibitors were administered continuously.
Johannes Vogt explains: “By gene mutation and pharmacological inhibition of ATX, we were able to observe a significant reduction in overeating and obesity. 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 behavior.”
Robert Nitsch sees the findings as an important step in the development of new drugs: “The data show that people with a disrupted synaptic LPA signaling pathway are more often overweight and suffer from type II diabetes. This is a strong indication of the possible therapeutic success of ATX inhibitors, which we are currently developing together with the Hans Knöll Institute in Jena for use in humans.’
These findings on the excitation control of neuronal networks in eating behavior by lysophospholipids and the resulting new therapeutic possibilities could not only contribute to the treatment of eating disorders, but also to neurological and psychiatric diseases.
About this news from neuroscientific research
Author: Eva Schissler
Source: University of Cologne
Contact: Eva Schissler – University of Cologne
Picture: The picture is attributed to Johannes Vogt
See also
Original research: Closed access.
“AgRP neurons control feeding behavior at cortical synapses via peripherally derived lysophospholipids” by Johannes Vogt. natural metabolism
abstract
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. Whether changes in peripheral metabolism affect brain lipid levels and cortical excitability remains unknown.
Here we show that concentrations of lysophosphatidic acid (LPA) species in blood and cerebrospinal fluid are elevated after overnight fasting and result in higher cortical excitability. LPA-related cortical excitability increases fasting-induced hyperphagia and is decreased after inhibition of LPA synthesis.
Mice carrying a human mutation (Prg-1R346T), resulting in higher synaptic lipid-mediated cortical excitability, shows 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 post-fasting effects of LPA are under the control of hypothalamic agouti-related peptide (AgRP) neurons. Depletion of AgRP-expressing cells in adult mice decreases fasting-induced elevation in circulating LPAs as well as cortical excitability while blunting hyperphagia.
These results demonstrate a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability, and unveil an alternative non-neuronal pathway through which the hypothalamus can exert a robust influence on the cortex and thereby influence feeding.
