A unique delivery of brain-derived neurotrophic factor (BDNF) in a brain region called the hypothalamus improved metabolism in mice with some symptoms of Prader-Willi syndrome (PWS), according to a new study.
Gene therapy improvements translated into less weight gain and healthier body composition, suggesting that “BDNF is a promising molecular target for PWS and other genetic forms of obesity,” wrote Researchers.
The study, “Hypothalamic AAV-BDNF Gene Therapy Improves Metabolic Function and Behavior in the Magel2-null Mouse Model of Prader-Willi Syndromewas published in Molecular therapy – Methods and clinical development.
PWS is caused by the loss or defects of a region of chromosome 15 called the PWS locus. It contains genes that control sleep, metabolism, appetite, growth, intellectual abilities and social behavior.
This means that when these genes are missing or faulty, there can be symptoms such as learning difficulties, behavioral problems, developmental delay and excessive appetite which usually leads to weight gain and obesity.
BDNF is known to help maintain the health of the hypothalamus by allowing nerve cells, or neurons, to grow, mature, and stay alive. Researchers in the United States and Canada believed that introducing BDNF into the hypothalamus might alleviate the symptoms of the disease.
To test this, they turned to a mouse model in which MAGEL2, a gene at the PWS locus that plays a role in weight control, was deleted (null). These mice mimic some of the hallmark symptoms of the disease in humans.
Delivering the BDNF gene
The scientists delivered the gene encoding BDNF, which they tagged with a yellow fluorescent tag, on board an adeno-associated virus (AAV) directly into the hypothalamus. The delivery package included an “autoregulatory” element that allows BDNF to be produced in the right amount in the hypothalamus, reflecting the body’s physiological needs. They used an AAV with the fluorescent label only to compare as a control.
Delivery of the BDNF gene resulted in a 4.5-fold increase in the amount of BDNF in the hypothalamus compared to control AAV.
From three weeks and up to 23 weeks (nearly six months) after the start of the study, MAGEL2-null mice that had the BDNF The gene delivered to the hypothalamus ate less than those who received the control AAV. They were also lighter, had less fatty tissue, more lean body mass, and expended more energy than control mice.
The researchers then looked at changes in glucose (sugar) metabolism, which refers to all the chemical reactions involved in making or breaking down glucose. They found that BDNF-treaty MAGEL2-null mice were more sensitive (responsive) to insulin than wild-type (healthy) mice or those with control AAV. Insulin is a hormone made by the pancreas that allows cells to absorb and use glucose.
When challenged with a bolus (a discrete amount given over a short period) of glucose, MAGEL2-null mice were unable to use anything. And even after an overnight fast, their blood sugar levels remained elevated — and higher than wild-type mice.
But BDNF gene delivery was able to reverse these effects, meaning the mice were able to better utilize glucose. Consistent with these results, these mice were more active and had significantly more adiponectin and less leptin in their blood. Adiponectin and leptin are hormones that control the amount of fat in the body. Adiponectin improves cells’ response to insulin, while leptin helps prevent hunger and regulate energy balance.
Compared to MAGEL2-null mice given the control AAV, less inclined to explore the environment and new objects than wild-type mice, those treated with BDNF were significantly more likely to monitor their surroundings. They also showed a tendency towards less depressive behavior.
“Together, these data suggest that up-regulation of hypothalamic BDNF may be effective in treating PWS-related metabolic abnormalities,” the team concluded.
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