Neuroscientists identify two key groups of neurons that help regulate appetite

_In a newly published study, Scientists from MIT have identified two key groups of neurons within the hypothalamus that help regulate appetite._ MIT neuroscientists have discovered that

brain cells called glial cells play a critical role in controlling appetite and feeding behavior. In a study of mice, the researchers found that activating these cells stimulates overeating,

and that when the cells are suppressed, appetite is also suppressed. The findings could offer scientists a new target for developing drugs against obesity and other appetite-related

disorders, the researchers say. The study is also the latest in recent years to implicate glial cells in important brain functions. Until about 10 years ago, glial cells were believed to

play more of a supporting role for neurons. “In the last few years, abnormal glial cell activities have been strongly implicated in neurodegenerative disorders. There is more and more

evidence to point to the importance of glial cells in modulating neuronal function and in mediating brain disorders,” says Guoping Feng, the James W. and Patricia Poitras Professor of

Neuroscience. Feng is also a member of MIT’s McGovern Institute for Brain Research and the Stanley Center for Psychiatric Research at the Broad Institute. Feng is one of the senior authors

of the study, which appears in the October 18 edition of the journal _eLife_. The other senior author is Weiping Han, head of the Laboratory of Metabolic Medicine at the Singapore Bioimaging

Consortium in Singapore. Naiyan Chen, a postdoc at the Singapore Bioimaging Consortium and the McGovern Institute, is the lead author. TURNING ON APPETITE It has long been known that the

hypothalamus, an almond-sized structure located deep within the brain, controls appetite as well as energy expenditure, body temperature, and circadian rhythms including sleep cycles. While

performing studies on glial cells in other parts of the brain, Chen noticed that the hypothalamus also appeared to have a lot of glial cell activity. “I was very curious at that point what

glial cells would be doing in the hypothalamus, since glial cells have been shown in other brain areas to have an influence on regulation of neuronal function,” she says. Within the

hypothalamus, scientists have identified two key groups of neurons that regulate appetite, known as AgRP neurons and POMC neurons. AgRP neurons stimulate feeding, while POMC neurons suppress

appetite. Until recently it has been difficult to study the role of glial cells in controlling appetite or any other brain function, because scientists haven’t developed many techniques for

silencing or stimulating these cells, as they have for neurons. Glial cells, which make up about half of the cells in the brain, have many supporting roles, including cushioning neurons and

helping them form connections with one another. In this study, the research team used a new technique developed at the University of North Carolina to study a type of glial cell known as an

astrocyte. Using this strategy, researchers can engineer specific cells to produce a surface receptor that binds to a chemical compound known as CNO, a derivative of clozapine. Then, when

CNO is given, it activates the glial cells. The MIT team found that turning on astrocyte activity with just a single dose of CNO had a significant effect on feeding behavior. “When we gave

the compound that specifically activated the receptors, we saw a robust increase in feeding,” Chen says. “Mice are not known to eat very much in the daytime, but when we gave drugs to these

animals that express a particular receptor, they were eating a lot.” The researchers also found that in the short term (three days), the mice did not gain extra weight, even though they were

eating more. “This raises the possibility that glial cells may also be modulating neurons that control energy expenditures, to compensate for the increased food intake,” Chen says. “They

might have multiple neuronal partners and modulate multiple energy homeostasis functions all at the same time.” When the researchers silenced activity in the astrocytes, they found that the

mice ate less than normal. Suzanne Dickson, a professor of neuroendocrinology at the University of Gothenburg in Sweden described the study as part of a “paradigm shift” toward the idea that

glial cells have a less passive role than previously believed. “We tend to think of glial cells as providing a support network for neuronal processes and that their activation is also

important in certain forms of brain trauma or inflammation,” says Dickson, who was not involved in the research. “This study adds to the emerging evidence base that glial cells may also

exert specific effects to control nerve cell function in normal physiology.” UNKNOWN INTERACTIONS Still unknown is how the astrocytes exert their effects on neurons. Some recent studies have

suggested that glial cells can secrete chemical messengers such as glutamate and ATP; if so, these “gliotransmitters” could influence neuron activity. Another hypothesis is that instead of

secreting chemicals, astrocytes exert their effects by controlling the uptake of neurotransmitters from the space surrounding neurons, thereby affecting neuron activity indirectly. Feng now

plans to develop new research tools that could help scientists learn more about astrocyte-neuron interactions and how astrocytes contribute to the modulation of appetite and feeding. He also

hopes to learn more about whether there are different types of astrocytes that may contribute differently to feeding behavior, especially abnormal behavior. “We really know very little

about how astrocytes contribute to the modulation of appetite, eating, and metabolism,” he says. “In the future, dissecting out these functional differences will be critical for our

understanding of these disorders.” Reference: “Direct modulation of GFAP-expressing glia in the arcuate nucleus bi-directionally regulates feeding” by Naiyan Chen, Hiroki Sugihara, Jinah

Kim, Zhanyan Fu, Boaz Barak, Mriganka Sur, Guoping Feng and Weiping Han, 18 October 2016, _eLife_. DOI: 10.7554/eLife.18716 NEVER MISS A BREAKTHROUGH: JOIN THE SCITECHDAILY NEWSLETTER.