Almost everyone knows the feeling. You're at a restaurant or a holiday meal, and your stomach is telling you it's full, so logically you know you should stop eating.
But what you're eating tastes so good, or your friends and family are still eating, or you don't get this treat very often. So you keep going.
A new study explores the mystery of why this happens, at the most basic level in the brain. It shows that two tiny clusters of cells battle for control of feeding behavior -- and the one that drives eating overpowers the one that says to stop.
It also shows that the brain's own natural opioid system gets involved - and that blocking it with the drug naloxone can stop over-eating.
The researchers studied mice, not over-eating humans. But they do note that the findings could help inform the fight against the global obesity epidemic.
The two groups of brain cells they looked at, called POMC and AgRP, are next-door neighbors in a deep brain region called the arcuate nucleus, or Arc, within a larger region called the hypothalamus, which is a master regulator of motivated behaviors.
"We used a transgenic approach to specifically address the POMC neurons for optogenetic stimulation, and we expected to see a decrease in appetite. Instead, we saw a really remarkable effect," senior author says. "The animals ate like crazy; during the half hour after stimulation, they ate a full day's supply of food."
Previous research showed that the Arc region, and specifically POMC and AgRP neurons, play key roles in feeding behavior.
The gene called POMC (short for pro-opiomelanocortin) has multiple functions: it encodes a stress hormone called ACTH, a natural opioid called beta-endoprhin, and several other molecules called melanocortins.
POMC's products get opposition from products of the AgRP gene, whose name is short for Agouti-Gene-Related Peptide. In general, POMC acts like a brake on feeding when it gets certain signals from the body, and AgRP acts like an accelerator pedal, especially when food is scarce or it's been some time since a meal.
But the new study shows for the first time how their activity relates to one another, thanks to a technique called optogenetics. By focusing on unique molecular features of a particular group of neurons, it makes it possible for scientists to target, or address, those cells specifically and activate them selectively.
The serendipitous optogenetic finding about the over-eating mice set off a search for the reason why they overate.The answer was that while they were optogenetically stimulating the POMC cells, they were also unintentionally stimulating a subset of AgRP cells nearby. The two types of cells originate from the same parent cells during embryonic development. That common heritage meant that the transgenic approach by the authors used to address POMC captured not only the POMC neurons but also a segment of the AgRP neuronal system.
In other words, they had turned on both the brake and the gas pedal for eating. When both types of cell got activated, the "keep eating" signal from AgRP cells overpowered the "stop eating" signal from POMC cells. "When both are stimulated at once, AgRP steals the show," says the senior author.
Then the researchers used a different technique, addressing the cells with an injected virus rather than a transgene, to focus the optogenetic stimulation on just POMC neurons and ensure that AgRP neurons didn't get activated.
They found that stimulating just POMC cells caused a significant decrease in eating - and were surprised at how rapidly it happened. The team also used a new method called CLARITY to visualize in 3-D the pathways that start from POMC and AgRP neurons. These pathways of neurons, once activated, can trigger either a sense of feeling full - called satiety -- or the drive to eat. They stitched together images of activated neurons in a computer, to create 3-D videos that show the neurons' reach.
Then, the researchers used a method called c-fos activation to dig deeper into the downstream effects of POMC and AgRP neuron activation - and showed that its effects spread throughout the brain, including in the cortex, which governs function like attention, perception, and memory.
Since POMC encodes a natural opioid (B-Endorphin), the authors asked whether activation of this system triggers the body's own natural painkiller system, called the endogenous opioid system. They found that activation of POMC blocked pain, but that this was reversed by the opioid antagonist drug naloxone.
Interestingly, the activation of AgRP, which triggered feeding, also turned on the opioid system in the brain. "When we administered naloxone, which blocks opioid receptors, the feeding behavior stopped," says the senior author. "This suggests that the brain's own endogenous opioid system may play a role in wanting to eat beyond what is needed."
The involvement of the cortex and opioid systems lead the authors to think about how the results might relate to the human experience. Though mice and humans are very different, they peculate that the bombardment of our senses with sights and smells related to food, and the social interactions related to food, may be involved in encouraging overeating.
Perhaps, these factors combine to trigger us to become interested in eating when we're not even hungry, and the battle between the "stop" and "keep going" signals is lost.
"Our work shows that the signals of satiety - of having had enough food - are not powerful enough to work against the strong drive to eat, which has strong evolutionary value," the senior author says and notes that other researchers are looking at opiate receptor blockers as potential diet aids, and that it's also important to study the pathways that are activated by the products of both POMC and AgRP cells, as well as individual differences in all these systems.
Many studies in humans have looked at the metabolic aspects of the drive to eat, and overeat - for instance, the metabolic signals that travel between the body and brain in the form of peptides such as leptin and ghrelin. But the senior author says there appears to be a strong neural system involved in overeating that results from perceptual, emotional and social triggers, and that is not receiving sufficient scientific attention.
How urge to eat overpowers a signal to stop
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