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'Off Switch' for Appetite Accidentally Discovered in Brain Enzyme


Researchers stumbled upon brain cells which seem to be able to turn a mouse's appetite on and off. Jessica Florence/Getty Images
Researchers stumbled upon brain cells which seem to be able to turn a mouse's appetite on and off. Jessica Florence/Getty Images

Across the board, people are a lot fatter than they used to be. More than one third of adults in the United States are obese — up from just 15 percent in 1990 — as are one in six children. Obesity leads to all kinds of health problems, including heart disease, type 2 diabetes, and some types of cancer, and although everybody has a pet theory about what's causing this worldwide epidemic, nobody can explain it definitively.

However, a new study published in the journal Science describes the accidental discovery of a new type of nerve cell in mouse brains. This nerve cell seems to control how much food the mice eat before they're satiated.

"It was a fun example of serendipity in science," says Dr. Richard L. Huganir, co-author of the paper and director of the Johns Hopkins University School of Medicine neuroscience department, of the fortuitous discovery.

Up to now, the focus of Huganir's lab has been the study of learning and memory. His research team set out to investigate the role of an enzyme called O-GlcNAc transferase (OGT), which, outside the brain functions as a nutrient sensor in cells, but very little was known about how OGT works inside the brain. The research team wanted to know how the enzyme worked in the hippocampus and cortex, the brain's learning and memory centers.

Using knockout mice — genetically modified mice in which a specific gene has been deleted and replaced with an artificial piece of DNA — the scientists "knocked out" a gene called aCaMKII that codes for OGT in the hippocampus and cortex, and waited until the mice were ready to study. But while they were waiting for this gene deletion to take effect, a Ph.D. student came into his office after noticing a perplexing problem.

"About two weeks after we knocked out the gene, my student came in and told me the mice were getting really fat," says Huganir. "And it wasn't something you could ignore — these mice were eating about twice as much as normal. By the end of three weeks, their weight had doubled. Even though these mice were not couch potatoes — I'd say they're more active than their littermates — the weight gain was all fat buildup, not muscle mass."

It turns out that these while the mice were eating the correct number of meals every day — about 18, on average, which suggests mice have a pretty sweet life — they were eating for twice as long, taking in twice the calories. The gene the researchers "knocked out" had inadvertently tampered with the hypothalamus, the part of the brain that controls many autonomic processes like sleep, temperature, metabolism, and feeding.

"It's been known for decades that there are cells in the hypothalamus important for feeding behavior," says lead author Olof Lagerlöf, the Ph.D. student who made the initial observation. "But as we haven't been able to tell which cells are important for feeding from those that control other functions in the hypothalamus, like sleeping, it's been difficult to understand the molecular and cellular basis of food intake."

But in these mice whose aCaMKII gene had been knocked out, the researchers were able to find OGT missing from cells in a small region of the hypothalamus called the paraventricular nucleus. The absence of OGT from these specialized nerve cells was making their synapses fire very weakly, rendering them nearly useless.

"This suggested to us that these cells that weren't firing were responsible for controlling satiety in these mice," says Huganir.

The "serendipitous" results of this study may help future researchers better understand why some people eat more or less.

"The fact that so many people are overweight today is probably a product of our attitude towards food and what we choose to eat," says Lagerlöf. "However, some may have a background making them more vulnerable to the side effect of eating large meals often. That said, it would be a great help to very many people if we could develop aids that help people to eat less every meal. The health benefits would be immense." 



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