Researchers reveal how a single gene mutation leads to uncontrolled obesity

March 18, 2012, Georgetown University Medical Center

Researchers at Georgetown University Medical Center have revealed how a mutation in a single gene is responsible for the inability of neurons to effectively pass along appetite suppressing signals from the body to the right place in the brain. What results is obesity caused by a voracious appetite.

Their study, published March 18th on 's website, suggests there might be a way to stimulate expression of that gene to treat obesity caused by uncontrolled eating.

The research team specifically found that a mutation in the brain-derived neurotrophic factor (Bdnf) gene in mice does not allow brain to effectively pass and insulin chemical signals through the brain. In humans, these hormones, which are released in the body after a person eats, are designed to "tell" the body to stop eating. But if the signals fail to reach correct locations in the hypothalamus, the area in the brain that signals satiety, eating continues.

"This is the first time in dendrites, tree-like extensions of neurons, has been found to be critical for control of weight," says the study's senior investigator, Baoji Xu, Ph.D., an associate professor of pharmacology and physiology at Georgetown.

"This discovery may open up novel strategies to help the brain control body weight," he says.

Xu has long investigated the Bdnf gene. He has found that the gene produces a growth factor that controls communication between neurons.

For example, he has shown that during development, BDNF is important to the formation and maturation of synapses, the structures that permit neurons to send chemical signals between them. The Bdnf gene generates one short transcript and one long transcript. He discovered that when the long-form Bdnf transcript is absent, the growth factor BDNF is only synthesized in the cell body of a neuron but not in its dendrites. The neuron then produces too many immature synapses, resulting in deficits in in mice.

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 . The intent is to keep the leptin and insulin 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 , 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 ," Xu says. "We have opened the door to both new avenues in basic research and clinical therapies, which is very exciting."

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JVK
not rated yet Mar 18, 2012
I am reminded of a role for both BDNF and methylation in memory formation. DNA methylation inhibitors block the induction of long-term potentiation in the hippocampus and induce acute changes in the methylation status of Bdnf promoters (e.g. two genes implicated in the induction of hippocampal synaptic plasticity). This suggests to me that nutrient-chemical-induced modifications of DNA and also its modification by pheromones might help to explain both learning and the development of obesity at the molecular level. Clearly, evolution has conserved these mechanisms for food-chemical calibration of individual survival and pheromone standardization/control of speciation via experience driven changes in hormones that affect behavior in mammals. And this conservation can be backtracked via olfactory receptor genes that vary with nutrients in ecological niches that contribute to speciation. Are errors in BDNF linked to odor learning/memory via olfactory receptor-mediated events?

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