Researchers, for the first time, have demonstrated in mice that a protein called brain-derived neurotrophic factor (BDNF) is critical in managing satiety, and is the main cause behind obesity and overeating.
The study, led by Maribel Rios, PhD, and assistant professor of neuroscience at the Sackler School of Graduate Biomedical Sciences at Tufts University School of Medicine in Boston and colleagues, revealed that it is the lack of BDNF that is responsible for triggering overeating and obesity.
AdvertisementResearchers showed that the mice in which the BDNF gene was deleted in two of the primary appetite-regulating regions of the brain ate more and became significantly heavier than their counterparts.
"Prior to this study, we knew that the global lack of BDNF and/or its receptor during development leads to overeating and obesity in young mice. However, it remained unclear and controversial whether BDNF mediated satiety in adult animals. Our recent findings demonstrate that BDNF synthesis in the ventromedial (VMH) and dorsomedial hypothalamus (DMH) is required for normal energy balance," said Rios.
"Additionally, because the mice examined in this study were genetically altered in adulthood, 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.
She said that the obesity exhibited by BDNF-depleted mice appeared to be boosted just from over-consumption of calories.
"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," said Rios.
In a series of related experiments, the researchers used advanced molecular and surgical techniques to measure levels of BDNF mRNA, a precursor of active BDNF protein, in relation to nutritional status.
It was confirmed later that glucose acts directly in the brain, rather than through peripheral pathways, to increase BDNF expression.
"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. These results suggest that BDNF is a fast-acting signal inducing neuronal activity within neural circuits involved in appetite control," stated Rios.
She added: "Mice with site-specific perturbation of BDNF expression did not exhibit behavioral abnormalities typically observed in mice with global deletion of the Bdnf gene throughout the brain, such as hyperaggression, depressive-like behavior, and hyperactivity. The absence of these behaviors suggests that BDNF expression in the VMH and DMH is not required for regulation of non-appetite-related behaviors."
Rios also said that BDNF had a prominent role to play in the regulation of energy balance in adult mice.
"Our results establish that BDNF plays a prominent and direct role in the regulation of energy balance in adult mice. 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," she said.
However, Rios added that there was a need for additional studies to further pinpoint the cellular and molecular targets of BDNF action.
"This work brings us closer to elucidating the brain pathways that rely on BDNF to modulate food intake. The relevance of the BDNF signaling pathway in human disease is highlighted by the obesity exhibited by certain humans carrying mutations or abnormalities in the genes coding for BDNF or its receptor," she said.
She added: This is bound to be an important area of obesity research as more than a quarter on the American population has been estimated to carry mutations in the Bdnf gene."
The study is published in the recent issue of The Journal of Neuroscience.
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