Why does desire to keep eating overpower the signal that says we are full? New research discovers that it involves a struggle between two neighboring groups of brain cells in which the brain’s opioid system also has a role. It also found that the drug naloxone, by blocking the opioid system, halted overeating. The study, which features in the Proceedings of the National Academy of Sciences, was carried out on mice, but the scientists believe that the findings will help us better understand similar mechanisms in humans. “Our work,” explains senior study author Prof Huda Akil, a neuroscientist in the Department of Psychiatry at the University of Michigan Molecular and Behavioral Neuroscience Institute in Ann Arbor, “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.” Being overweight or obese increases the risk of developing several long-lasting conditions, such as cardiovascular diseases and type 2 diabetes, as well as cancer. Carrying too much weight is a worldwide public health problem, affecting low and middle-income countries as well as high-income ones. World Health Organization (WHO) estimates from 2016 suggest that 39 percent of adults globally are overweight and 13 percent are obese. The pressure to better understand drivers of obesity, such as the brain’s role in regulating eating , has never been greater. Among these, note the study authors, are ‘the mechanisms that modulate both the initiation and the cessation of feeding.’ Professor Akil and her colleagues focused on two small groups of adjacent nerve cells, or neurons, in the hypothalamus, which is a small brain region that is involved in several functions, such as the control of “motivated behaviors.” The two cell groups are called pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) cells. They reside in a region of the hypothalamus known as the arcuate nucleus (Arc). Scientists already knew that the two groups and the Arc were somehow involved in the “control of feeding.” Indeed, in previous work, some of the team had already revealed that on receipt of certain signals, POMC neurons act “like a brake” on eating and AgRP neurons act like the gas pedal, especially when a lot of time has elapsed since the last feed. However, what remained unclear was how these two groups interacted. A tool called optogenetics helped the investigators map the mechanism’s signals by using laser light to activate and deactivate selected cells in mice that were overeating. They revealed that when they activated POMC cells, this also activated nearby AgRP cells. This meant that the gas pedal and the brake on feeding were engaged at the same time, and the result was that the gas pedal won. “When both are stimulated at once, AgRP steals the show,” Prof Akil explains. With a different optogenetic method, the scientists saw that they could trigger POMC cells without activating nearby AgRP cells. This led to a rapid and “significant decrease” in the mice’s eating. Using a visualization tool, they also made detailed maps of the pathways involved. They produced a 3-D map of pathways that begin in POMC and AgRP. Once active, these signaling routes trigger either the feeling of fullness or an urge to eat. In further tests, the investigators explored the signals that are “downstream” of POMC and AgRP cell activation, revealing that their influence extends widely in the brain, encompassing even regions in the cortex that control perception, memory, and attention. In a final set of experiments, the team revealed that activating AgRP also switches on the brain’s opioid system. Giving the rodents the opioid receptor blocker naloxone stopped the feeding behavior. “This suggests that the brain’s own endogenous opioid system may play a role in wanting to eat beyond what is needed,” notes Prof. Akil. Typically, studies into the metabolic drivers of eating and overeating tend to focus on hormones such as ghrelin and leptin. These findings, however, suggest that brain circuits, or “neural systems,” also appear to play an important role. These could be reacting to emotional, social, and perceptual signals. Prof. Akil urges for further research into this aspect of overeating. Published in Daily Times, September 25th 2018.