A compound that makes people lose weight may work by stimulating the growth of new cells in the brain's appetite-control center. If the finding holds up, it would be one of the first demonstrations of the effects of new neuron growth in the adult mammalian brain.
The compound under debate, ciliary neurotrophic growth factor (CNTF), was first identified as a protein that helps neurons survive and specialize. But researchers studying CNTF found an unexpected side effect: Mice and people given the compound lost their appetite and shed dramatic amounts of weight. And unlike most weight loss drugs, those taking CNTF or a related compound called Axokine didn't have the urge to binge as soon as treatment stopped. "Many of us found the effect absolutely stunning," says Jeffrey Flier of Harvard Medical School in Boston, Massachusetts.
Hopes for Axokine dimmed when patients in larger trials developed antibodies to the drug and stopped responding. But Flier and colleagues Maia Kokoeva and Huali Yin were still interested in why Axokine and CNTF work the way they do. So the researchers gave overweight mice a 7-day treatment of CNTF along with a compound that marks newly-divided cells. The mice lost weight and kept it off for at least 2 weeks after treatment stopped. When the researchers examined the brains of the mice, they found that those given CNTF had about six times more new cells in the hypothalamus, a brain region that regulates metabolism, than control animals. Some new cells seemed to be neurons that respond to leptin, a hormone that regulates appetite by signalling cells in the hypothalamus. The team also gave one group of mice CNTF along with a compound that blocks cell division. Those mice initially lost weight, but after going off both drugs, they gained even more weight than control mice, the team reports 28 October issue of Science.
Flier suggests CNTF has a dual function: During treatment, it suppresses appetite by activating the leptin-responsive pathway in the hypothalamus. And by triggering the growth of new leptin-responsive neurons there, it makes the body more sensitive to the appetite-suppressive effects of leptin even after treatment is stopped.
"It's a very clever set of experiments," says neuroscientist Jeffrey Macklis of Massachusetts General Hospital and Harvard Medical School. However, he thinks CNTF is supporting the survival of immature brain cells rather than prompting new cell growth. Moreover, George Yancopoulos of Regeneron Pharmaceuticals in Tarrytown, New York, the company that developed Axokine, challenges Flier's understanding of how CNTF works. The weight-loss effect, he says, can be explained by CNTF's suppression of appetite-increasing molecules like the signaling factor NPY, not by the stimulation of new neuron growth.