A new study from the University of Pennsylvania has uncovered the biological mechanism by which our gut communicates with the brain to regulate the sensation of hunger. The researchers also discovered a novel combination of hormones that can mimic the signal sent to our brain telling it that enough food has been consumed.

Scientists have uncovered great insights into our body's appetite-regulating mechanisms in recent years. We now know that not only is the hypothalamus the brain's hunger controlling headquarters, but a concentration of neurons in the region called agouti-related protein-expressing neurons (AgRP) are key in managing energy expenditure and feelings of hunger.

"When these neurons are firing, they're basically telling you, 'You'd better go get food; you're starving,'" says J. Nicholas Betley, one of the authors of the new study.

This new research set out to understand what mechanisms are involved in turning these neurons on and off in relation to the nutrient value of the food being consumed. Earlier work from the same team discovered that simply smelling or seeing food could reduce AgRP neuron activity.

New experiments working with mice looked at AgRP activity after the animals were fed an unfamiliar, calorie-free gel. Initial feeding of the food showed a direct decrease in AgRP activity, but this decrease only lasted on average around 200 seconds before the appetite neurons reactivated. This suggested that once the stomach had recognized the foodstuff as lacking in calories it communicated to the brain to recommence hunger sensations so the animal could further obtain sufficient nutrients.

Across the trial it was seen that the mice learned to associate certain foodstuffs with their calorie characteristics so AgRP activity quickly became anticipatory, either rising or falling according to prior knowledge of what was about to be consumed.

"In a single trial, the circuits in the brain's sensory system learn to associate the visual or olfactory stimulus of the [gel] with calories," explains Betley. "If they get the caloric kind first and then see the calorie-free kind, they predict the nutrients because the flavor is the same, the taste is similar. It takes 200 seconds for the animal to realize that whatever has hit its gut isn't doing what it should be doing and the activity of those neurons comes back."

The next step in the research was to uncover what process the gut was using to signal to the brain that the food consumed didn't contain sufficient nutrients. Three hormones, emitted during digestion, were identified as directly contributing to significant reductions in AgRP neuron activity. A low-dose cocktail of the three hormones was subsequently developed by the researchers and shown to reduce AgRP activity with very little side effects when given to the mice.

As well as developing drugs to mimic these gut-brain signals, further research will examine ways to design weight loss strategies that can fundamentally minimize AgRP neuron activity, and therefore hunger.

"It would be interesting to see whether consuming smaller meals more frequently might lead to less activity in the neurons and thus less food intake overall," suggest Betley. "Or maybe we can develop better combinations of foods or better ways of eating so we can avoid that 9 p.m. binge on Oreo cookies when you've had a really great diet all day."

The research was published in the journal Cell Reports.