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The study focuses on ciliary neurotrophic factor (CNTF), a brain chemical that has long been used in the lab to help keep neural stem cells alive. Its ability to prevent motor neurons from dying prompted researchers to explore its use as a treatment for amyotrophic lateral sclerosis (ALS). The therapy failed, but one of the drug’s side effects pointed to a new application: it produced severe weight loss in patients. Further studies in animals showed that lower doses of the drug could be effective as an obesity treatment.
CNTF seemed to act on the same molecules and regions of the brain as the appetite-regulating hormone leptin. “There were many similarities in signaling pathways between how leptin worked and how CNTF worked,” Flier said. But CNTF was not dependent on leptin receptors, suggesting it might be able to circumvent leptin resistance found in obesity. In response to these discoveries, the pharmaceutical company Regeneron brought a version of CNTF called Axokine through clinical trials. Despite promising early results, many of the patients developed antibodies to the drug and its development was halted.
But one aspect of Axokine’s effects drew Flier’s attention. Unlike other weight loss drugs, this one still worked after patients stopped taking it. After treatment, both animals and humans continued to lose weight and maintained weight loss for weeks or months. This observation prompted Flier and postdoctoral fellow Maia Kokoeva to investigate whether CNTF was causing a more permanent, long-term change in the brain. Since CNTF is a known growth factor, the simplest explanation was that it may be causing the growth of new cells.
Uncovering New Growth
To test their hypothesis, the team gave adult mice a high-fat diet for two months and then treated them with CNTF and a marker of cell proliferation, BrdU, that is commonly used to detect neurogenesis. After continuously infusing the cerebrospinal fluid of mice with the compounds for a week, they examined the brains of the mice about two weeks after stopping the treatment and compared them with mice injected with BrdU alone.
The team found new cells in both sets of animals, but they detected a marked increase in the number of cells that were positive for BrdU, which incorporates into the DNA of dividing cells, in animals treated with CNTF. The cells appeared throughout the hypothalamus, concentrated in the arcuate nucleus, a region known to control energy balance. Many of the BrdU-positive cells were also positive for CNTF’s receptor and molecules involved in controlling energy balance. A substantial number of the new cells had characteristics of developing neurons, while others seemed to be glial cells.
The results, published in the Oct. 28 Science, draw a provocative connection between brain plasticity and the regulation of a seemingly hard-wired function of the brain.
The team repeated the experiment, but treated some mice with a chemical that prevents cells from dividing. Mice treated with the chemical lost weight during CNTF treatment, but rapidly regained weight after they stopped receiving it. “To us, it’s a strong suggestion that the new cell formation was an important requirement for the chronic weight loss,” Flier said.
When treated mice were given an injection of leptin, many of the new cells activated a molecule in the leptin signaling pathway. Flier suggests that signals within existing neurons produce the acute effects of the drug, but its long-term effects depend on producing new cells that function in leptin signaling. Mice that lacked leptin lost weight during treatment with CNTF, but regained the weight afterwards.
The Fertile Brain
Elizabeth Gould, professor of psychology and neurogenesis researcher at Princeton University, said the study is exciting because it shows that neurogenesis can occur in an area not widely accepted as capable of growing new neurons. Gould notes that Flier’s team delivered the BrdU marker directly into the brain, rather than into the skin as is commonly done. She speculated that the technique may increase the sensitivity and allow them to see neurogenesis that had not been detected before. And she noted it was interesting to see new neurons growing even without CNTF. “They did show that it happens in the controls,” she said. “But it happens at a much higher level in response to this treatment.”
CNTF is found naturally in the brain, mainly as a product of glial cells. Whether it regulates new cell formation under normal circumstances is completely unknown. But Flier said that the study opens up new questions about how neurogenesis and cell number in general might govern basic metabolic control mechanisms in the brain. The knowledge that new neurons can grow in adult brains is still fairly new, and plasticity research has focused mainly on areas of the brain that control learning, memory, and higher cognitive functions. “In the field of energy balance, the general approach is to assume that everyone’s hard-wired the same way,” Flier said. “Is it possible that some of the things we know that alter body weight could somehow be altering cell number?”