Using genetically altered mice, scientists in the US have shown that lack of brain-derived neurotrophic factor (BDNF), in certain parts of the brain, leads to overreating and may be a contributing factor to the rising obesity epidemic. The researchers said the study is relevant to humans because, for instance, a quarter of Americans are estimated to carry the mutated form of the BDNF gene.

The study is the work of Dr Maribel Rios, assistant professor of neuroscience at the Sackler School of Graduate Biomedical Sciences at Tufts University School of Medicine in Boston, Massachusetts, and colleagues and is published in the December 26th issue of The Journal of Neuroscience.

According to the US Centers for Disease Control and Prevention CDC), nearly one third of American adults are obese and another third are overweight. This is caused by an imbalance between the calories consumed and the calories needed by the body, with the excess unused calories deposited as body fat. This part of the problem is obvious and well studied.

However, less well studied is what regulates how much food people eat. Rios and colleagues have shown for the first time that lack of BDNF could be a key.

Scientists already knew that young mice that lacked BDNF and its receptor during development tended to eat more and become obese.

But what they did not know for certain was how BDNF affected appetite in older animals.

Rios and colleagues genetically altered adult mice by deleting the BDNF gene in two of the main appetite controlling parts of the brain: the ventromedial (VMH) and dorsomedial hypothalamus (DMH). These mice put on significantly more weight than their unaltered counterparts.

Rios explained:

“We were able to establish that BDNF acts as a satiety signal in the mature brain independently from its putative actions during development of the brain.”

“This important distinction might help define disease mechanisms and critical periods of intervention for the treatment and prevention of obesity disorders,” she added.

The researchers said the obesity in the BDNF depleted mice appeared to be due only to eating too many calories. There was no effect on energy expenditure due to BDNF depletion.

“Normal body weight was restored in mutant mice when food access was limited to that of normal mice, indicating that deletion of the BDNF gene in the VMH and DMH does not affect the expenditure side of the energy balance equation,” explained Rios.

The researchers used advanced techniques to measure the amount of BDNF mRNA, a precursor of the protein, in comparison to the food intake of the mice.

They found that during periods of fasting, the levels of BDNF mRNA went down. But when the mice ingested glucose, according to first author Thaddeus Unger, and a graduate student at the Sackler School, the researchers noticed a “rapid, but transient, increase in the expression of BDNF and its receptor”.

“These changes occurred specifically in the VMH, which is known to be involved in the regulation of food intake,” added Unger.

Unger, Rios and colleagues showed that glucose increased BDNF expression directly in the brain, and not via peripheral pathways.

“Direct administration of BDNF into the brain, also led to an immediate increase in the levels of an early-response gene and marker of nerve-cell activation in both the VMH and the DMH,” explained Rios.

“These results suggest that BDNF is a fast-acting signal inducing neuronal activity within neural circuits involved in appetite control,” she added.

Mice that had all of their BDNF genes knocked out in their brains became hyper aggressive and depressed, as expected. But this was not the case with mice that had BDNF genes knocked out only in selected parts of the brain.

“The absence of these behaviors suggests that BDNF expression in the VMH and DMH is not required for regulation of non-appetite-related behaviors,” said Rios.

This showed that BDNF played an important and direct role in regulating energy balance in adult mice, concluded the researchers.

“It appears that this signaling pathway acts, at least partly, through short-term mechanisms and that BDNF synthesis in the VMH and DMH is required for suppression of appetite,” added Rios.

Although further studies are needed to find the precise cellular and molecular targets of BDNF activity, this research has brought scientists closer to discovering the pathways that rely on BDNF to regulate food intake, said the researchers.

Rios suggested that this research is relevant to humans because obesity in humans has been linked to mutations or abnormality in genes coding for the BDNF protein or its receptor.

“This is bound to be an important area of obesity research as more than a quarter of the American population has been estimated to carry mutations in the BDNF gene,” explained Rios.

“Selective Deletion of Bdnf in the Ventromedial and Dorsomedial Hypothalamus of Adult Mice Results in Hyperphagic Behavior and Obesity.
Thaddeus J. Unger, German A. Calderon, Leila C. Bradley, Miguel Sena-Esteves, and Maribel Rios.
J. Neurosci. 2007 27: 14265-14274.

Click here for Abstract.

Sources: Tufts University press release, journal abstract.

Written by: Catharine Paddock