Summary: AgRP neurons in the hypothalamus control the release of endogenous lysophospholipids, helping to control the excitability of cerebral cortex neurons and stimulating the desire for food intake.
Source: University of Cologne
A group of researchers has developed an entirely novel approach to treating eating disorders.
The scientists 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 stimulates food intake.
In this process, the crucial step of the signalling 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 control food intake behaviour 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 worldwide, especially 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 proved ineffective.
A novel 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 the attendant 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 Münster) and Professor Thomas Horvath (Yale School of Medicine, New Haven, USA) has now shown that 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 at the synapse. Synaptic LPA signals stimulate specific networks in the brain, thus leading to increased food intake.
In the mouse model, after a period of fasting an increase in LPC in the blood led to an increase in stimulating LPA in the brain. These mice showed typical food-seeking behavior. Both could be normalized by administrating autotaxin inhibitors. Obese mice, on the other hand, lost weight when these inhibitors were administered continuously.
Johannes Vogt explained: ‘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 worked on for years, therefore also play a central role for eating behaviour.’
Robert Nitsch sees the findings as an important step towards new drug development: ‘The data show that people with a disturbed synaptic LPA signalling 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.’
These findings on the excitation control of neuronal networks in eating behaviour through lysophospholipids and the new therapeutic possibilities they suggest could in future contribute not only to treating eating disorders, but also neurological and psychiatric illnesses.
AgRP neurons control feeding behaviour 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 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.