Appetite Regulation Provides New Food for Thought

Identification of novel circuit components offers an alternative therapeutic target

obesity
A magnified view of a region of the hypothalamus showing astrocytes in red and NPY neurons in green. © 2017 A*STAR Singapore Bioimaging Consortium

A new set of brain cells that regulate appetite have been discovered by A*STAR researchers, offering an opportunity to expand our understanding of appetite and obesity and to investigate the interactions between the two major brain cell types, glia and neurons.

The researchers, led by Weiping Han of the A*STAR Singapore Bioimaging Consortium and Guoping Feng at MIT, manipulated a set of glial cells in the hypothalamus of mice known as astrocytes. Historically, astrocytes, like other glial cells, have been thought to play a passive, supporting role in the nervous system. However, research in the past decade has shown that these cells are active components of brain circuits.

To understand astrocytes’ role in controlling appetite, the researchers introduced custom receptors into the cells so they could be selectively activated using specific drugs. The mice ate three to four times more food when their astrocytes were activated, and they also looked for food more often and for longer. In a second experiment, the researchers inhibited the astrocytes and found that this reduced the mice’s appetite.

The researchers then measured the activity of two groups of neurons connected to the astrocytes that are known to help regulate appetite. One group, known as NPY neurons, became active when the astrocytes were stimulated, but there was no response in the second group, POMC neurons. However, the POMC neurons, which reduce appetite, are normally inhibited by the NPY neurons, which encourage appetite. The activation of NPY by the astrocytes may have strengthened this inhibition, counteracting any direct effect of the astrocytes on POMC. When the researchers blocked the inhibition, they found that POMC neurons were activated by the astrocytes, suggesting that appetite is regulated by a three-way circuit between astrocytes and the two neuron types.

Efforts to control appetite by using drugs that affect neurons have floundered because they have targeted the pleasure component of eating, which can have unwanted side effects on mood. “If drug- or receptor-screening experiments reveal unique receptors in astrocytes in the hypothalamus, that would allow people to engineer specific drugs to treat obesity or patients withhyperphagia,” says Naiyan Chen, the study’s lead author.

While therapeutic intervention remains a distant prospect, the discovery also creates an opportunity to learn about how glial cells interact with neurons. “We’re trying to unravel the detailed mechanisms that connect these two major cell types,” says Chen, adding that ignoring glial cells would miss half of what we need to learn about the brain.