Signaling pathway in the brain to control food intake decoded

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 (Image: Pixabay CC0)

(Image: Pixabay CC0)

Binge eating bye bye: Signaling pathway in the brain to control food intake decoded

A group of researchers has found a completely new approach to treating eating disorders. The scientists have demonstrated that a group of nerve cells in the hypothalamus (known as AgRP, agouti-related peptide neurons) control the release of endogenous lysophospholipids, which in turn control the excitability of nerve cells in the cerebral cortex, stimulating food intake. In this regard, the crucial step of this 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. In this context, the administration of autotaxin inhibitors can significantly reduce both the well-known overeating after fasting and obesity in animal models. The article ,,AgRP neurons control feeding behavior at cortical synapses via peripherally-derived lysophospholipids" has now been published 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 outcome such as heart attack, 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 even 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 the widespread disease of obesity.

In fact, the research team has found increased rates of obesity and associated type II diabetes in people with impaired synaptic LPA signaling. A group led by Prof. Johannes Vogt (Faculty of Medicine, University of Cologne), Prof. Robert Nitsch (Faculty of Medicine, University of Münster) and Tamas 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 control the amount of lysophosphatidylcholine (LPC) in the blood. Through active transport, LPC enters the brain, where it is converted by the enzyme autotaxin (ATX) into LPA, which is active at the synapse. Synaptic LPA signals lead to stimulation of specific networks in the brain and thus to increased food intake.

After a period of fasting in the mouse model, an increase in blood LPC led to an increase in brain LPA stimulating arousal. These mice showed typical food-seeking behavior. Both could be normalized by administration of autotaxin inhibitors. Obese mice, on the other hand, lost weight sustainably when these inhibitors were administered continuously. Johannes Vogt explains: "We have been able to show a significant reduction in overeating and obesity via gene mutation and pharmacological inhibition of ATX. Our fundamental findings on LPA-controlled excitability of the brain, which we have developed over many years, therefore also play a central role in eating behavior." Robert Nitsch associates the findings with an important therapeutic perspective towards new drug development: "In fact, the data show that people with a disturbed synaptic LPA signaling pathway are more likely to be overweight and suffer from type II diabetes. This is a strong indication of a possible therapeutic success by ATX inhibitors, which we are currently developing together with the Hans Knöll Institute in Jena for application in humans."

These findings on the excitation control of neuronal networks of eating behavior by lysophospholipids and a new possibility of their therapeutic correction may be relevant in the future not only for eating disorders but also for neurological and psychiatric diseases.

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