No More Binge Eating: AgRP neurons stimulates food intake

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.

Agouti-related peptide (AGRP)-expressing neurons are activated by fasting—this causes hunger1,2,3,4, an aversive state that motivates the seeking and consumption of food5,6. Eating returns AGRP neuron activity towards baseline on three distinct timescales: rapidly and transiently following sensory detection of food cues6,7,8, slowly and longer-lasting in response to nutrients in the gut9,10, and even more slowly and permanently with restoration of energy balance9,11. The rapid regulation by food cues is of particular interest as its neurobiological basis and purpose are unknown.

Given that AGRP neuron activity is aversive6, the sensory cue-linked reductions in activity could function to guide behaviour. To evaluate this, we first identified the circuit mediating sensory cue inhibition and then selectively perturbed it to determine function. Here, we show that a lateral hypothalamic glutamatergic → dorsomedial hypothalamic GABAergic (γ-aminobutyric acid-producing)12 → AGRP neuron circuit mediates this regulation.

Interference with this circuit impairs food cue inhibition of AGRP neurons and, notably, greatly impairs learning of a sensory cue-initiated food-acquisition task. This is specific for food, as learning of an identical water-acquisition task is unaffected. We propose that decreases in aversive AGRP neuron activity6 mediated by this food-specific circuit increases the incentive salience13 of food cues, and thus facilitates the learning of food-acquisition tasks.

reference link : https://www.nature.com/articles/s41586-021-03729-3

Original Research: Closed access.
“AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids” by Johannes Vogt. Nature Metabolism