Discovery of key hunger pathway hints at drugs to block binge eating

Scientists probing the functions of neurons known to play a central role in hunger sensation have discovered a novel signaling pathway by which they influence tendencies to binge eat. The breakthrough raises the prospect of using drugs to suppress this function and temper food cravings, with obese mice treated in this way losing weight as a result.

The neurons at the heart of this study are called agouti-related peptide neurons (AgRP), which reside in the brain's hypothalamus and when activated promote feelings of hunger. This has seen AgRP implicated in some promising advances in the field of obesity research, with studies showing how hormones can be deployed to regulate feelings of fullness, how AgRP can be beneficially altered through exercise, and how the neurons may play a central role in "yo-yo" dieting.

The latest findings in this area come from an international research team led by Johannes Vogt at the University of Cologne, and began with observations of mice subjected to periods of fasting. These mice exhibited higher amounts of a biomolecule called lysophosphatidylcholine (LPC) in the blood, levels of which the scientists found are controlled by AgRP. These lipid molecules then travel to the brain where they are converted into lysophosphatidic acid (LPA) through an enzyme called autotaxin (ATX).

This process excites neurons in the brain's cerebral cortex, with the mice then showing typical food-seeking behaviors as a result. The scientists found that by treating the mice with an inhibitor of the ATX enzyme, they could normalize these behaviors. Obese mice given these treatments on a continual basis lost weight as a result.

"We saw a significant reduction in excessive food intake and obesity through gene mutation and pharmacological inhibition of ATX," said Vogt. "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 behavior."

Though these effects were observed in mice, the scientists have found evidence of similar mechanisms at play in humans. In subjects found to have impaired function of LPA signaling, the team report higher rates of obesity and type 2 diabetes, and say that work is underway on drugs that target this particular pathway.

"The data show that people with a disturbed synaptic LPA signaling pathway are more likely to be overweight and suffer from type 2 diabetes," said study author Professor Robert Nitsch. "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."

The research was published in the journal Nature.

Source: University of Cologne