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The brain and hunger

How the brain influences our eating habits and weight gain

Investigators pinpointed a set of molecules that wire the body weight centre of the brain
Brain cells involved in memory play an important role after a meal in reducing future eating behaviour

Two separate teams of researchers have identified how genes involved in neural development can affect body weight and how brain cells involved in memory play an important role after a meal in reducing future eating behaviour. The first team – led by investigators at the University of Cambridge and Children's Hospital Los Angeles (CHLA) have pinpointed a set of molecules that wire the body weight centre of the brain.

In a study, ‘Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance’, published in the journal Cell, Dr Sadaf Farooqi of the University of Cambridge and CHLA's Sebastien Bouret, PhD led research teams to uncover key genes that guide the process of brain development.

"We know that the brain, in particular an area called the hypothalamus, has a very important role in the regulation of food intake and blood sugar," explained Bouret, who is also an associate professor of pediatrics at the Keck School of Medicine of USC. Researchers have focused on the hypothalamus for years in an effort to study the epidemic of obesity, which affects nearly 14 million children and adolescents in the United States. "What we don't yet understand is how these circuits in the hypothalamus are being organszed. We want to know how the brain puts itself together and what exactly governs that process."

Understanding this is key because circuits must be established properly in order for the brain to ultimately perform complex functions like maintaining proper weight.

Bouret's laboratory investigated how this precise wiring is achieved. Understanding how brain cells in the hypothalamus form these specific, complex connections - and how this process can be adversely affected - could provide insight into the development of childhood obesity.

Bouret studied a group of molecules called semaphorins, which are found in abundance in the developing hypothalamus. Brain cells release semaphorins to communicate with other brain cells. These messages act as a sort of road map, guiding cells towards or away from other cells.

Dr Sophie Croizier, who led the study in Bouret's lab, blocked semaphorin signaling in cells of the hypothalamus. She discovered that brain cells no longer grew the way they were supposed to, showing that semaphorin provides an essential map for them to follow. In addition to connections failing to establish, loss of semaphorin action in a preclinical model also caused elevated body weight.

"What we are seeing is that semaphorins are guiding and shaping development of hypothalamic circuits that ultimately regulate calorie intake," explained Bouret.

Professor Farooqi from the University of Cambridge was also analysing genetic information from individuals with obesity. Farooqi's team tested 1,000 DNA samples and found that individuals with early-onset obesity had more rare mutations in genes involved in semaphorin signalling than healthy individuals. The finding that people with obesity have rare mutations in semaphorin signalling shows that semaphorins are important in maintaining healthy body weight.

"We have now discovered the genes that establish the precise neural connections that form these circuits," added Dr Agatha van der Klaauw, who led the study in Farooqi's lab and is co-first author on the paper. "This work provides new insights into the development of hypothalamic circuits that regulate appetite and metabolism."

This multifaceted study reveals a much clearer picture of what occurs in the developing brain. Semaphorin signalling appears to shape the physical architecture of the brain and influence circuitry governing body weight.

Memory

In the second study, researchers led by Georgia State University, found that brain cells involved in memory play an important role after a meal in reducing future eating behaviour, a finding that could be key in understanding and fighting obesity.

The study, ‘Postmeal optogenetic inhibition of dorsal or ventral hippocampal pyramidal neurons increases future intake’,  suggests neurons in the hippocampus, a brain region that is vital for personal memories, inhibit future eating behaviour by consolidating the memory of the preceding meal. The findings are published in the journal eNeuro.

"Memories of recently eaten foods can serve as a powerful mechanism for controlling eating behaviour because they provide you with a record of your recent intake that likely outlasts most of the hormonal and brain signals generated by your meal," said Dr Marise Parent, associate director of the Neuroscience Institute and professor of neuroscience and psychology at Georgia State. "But surprisingly, the brain regions that allow memory to control future eating behaviour are largely unknown."

Hippocampal cells receive signals about hunger status and are connected to other brain areas that are important for starting and stopping eating. The researchers set out to determine if disrupting hippocampal function after a meal is eaten, when the memory of the meal is being stabilized, could promote eating later when these cells are functioning normally.

They tested this prediction using an advanced method called optogenetics that uses light to control individual cells. Using this technique to inhibit hippocampal cells after rats ate a meal caused the animals to eat their next meal sooner and caused them to eat almost twice as much food during that next meal, even though the cells were no longer inhibited while the animals ate their next meal. This effect was observed regardless of whether the rats were offered rodent chow, a sugar solution or water sweetened with saccharin.

The researchers found it interesting that rats would eat more saccharin after they interfered with their hippocampal function because this noncaloric sweetener produces very few gastrointestinal chemical signals generated by food. They concluded the effect they saw was most likely explained by an effect on memory consolidation, rather than by an impaired ability to process gastrointestinal messages.

The findings have significant implications for understanding the causes of obesity and the ways to treat it. This research supports the idea that techniques that promote hippocampal-dependent memories of what, when and how much one eats could prove to be promising strategies for reducing eating and promoting weight loss.

To access the first study, please click here

To access the second study, please click here (login maybe required)

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