Xu also found that the mice with the same Bdnf mutation grew to be severely obese.
Other researchers began to look at the Bdnf gene in humans, and large-scale genome-wide association studies showed Bdnf gene variants are, in fact, linked to obesity.
But, until this study, no one has been able to describe exactly how BDNF controls body weight.
Xu's data shows that both leptin and insulin stimulate synthesis of BDNF in neuronal dendrites in order to move their chemical message from one neuron to another through synapses. The intent is to keep the leptin and insulin chemical signals moving along the neuronal highway to the correct brain locations, where the hormones will turn on a program that suppresses appetite.
"If there is a problem with the Bdnf gene, neurons can't talk to each other, and the leptin and insulin signals are ineffective, and appetite is not modified," Xu says.
Now that scientists know that BDNF regulates the movement of leptin and insulin signals through brain neurons, the question is whether a faulty transmission line can be repaired.
One possible strategy would be to produce additional long-form Bdnf transcript using adeno-associated virus-based gene therapy, Xu says. But although this kind of gene therapy has proven to be safe, it is difficult to deliver across the brain blood barrier, he adds.
"The better approach might be to find a drug that can stimulate Bdnf expression in the hypothalamus," Xu says. "We have opened the door to both new avenues in basic research and clinical therapies, which is very exciting."
|Contact: Karen Mallet|
Georgetown University Medical Center