A new neuroscience study sheds light on the biological underpinnings of obesity¹. The in vivo study, published in the January 8 issue of The Journal of Neuroscience, reveals how a protein in the brain helps regulate food intake² and body weight. The findings reveal a potential new avenue for the treatment of obesity and may help explain why medications that are prescribed for epilepsy（癫痫） and other conditions that interfere³ with this protein, such as gabapentin and pregabalin, can cause weight gain. The protein -- alpha2/delta-1 -- has not been linked previously⁴ to obesity. A team led by Maribel Rios, Ph.D., associate professor in the department of neuroscience at Tufts University School of Medicine, discovered that alpha2/delta-1 facilitates the function of another protein called brain-derived neurotrophic factor (BDNF). A previous study by Rios determined⁵ that BDNF plays a critical role in appetite suppression, while the current study identifies a central mechanism⁶ mediating⁷ the inhibitory effects of BDNF on overeating.

 

"We know that low levels of the BDNF protein in the brain lead to overeating and dramatic obesity in mice. Deficiencies in BDNF have also been linked to obesity in humans. Now, we have discovered that the alpha2/delta-1 protein is necessary for normal BDNF function, giving us a potential new target for novel obesity treatments," said Rios, also a member of the cellular⁸ and molecular⁹ physiology¹⁰ and neuroscience program faculties¹¹ at the Sackler School of Graduate Biomedical Sciences at Tufts.

 

Rios and colleagues discovered that low levels of BDNF were associated with decreased function of alpha2/delta-1 in the hypothalamus, a brain region that is critical to the regulation of food intake and weight. When the team inhibited¹² the alpha2/delta-1 protein in normal mice, mice ate significantly more food and gained weight. Conversely, when the team corrected the alpha 2/delta-1 deficiency in mice with reduced BDNF levels, overeating and weight gain were mitigated¹³. In addition, blood sugar levels (related to diabetes¹⁴ in humans) were normalized.

 

"We blocked activity of the alpha2/delta-1 protein in mice using gabapentin. These mice ate 39 percent more food, and as a consequence gained substantially more weight than control mice over a seven-day period," said first author Joshua Cordeira, Ph.D., a graduate of the neuroscience program at the Sackler School and member of Rios's lab. This study is related to his Ph.D. thesis.

 

"When we re-introduced alpha2/delta-1 in obese¹⁵ mice lacking BDNF in the brain, we saw a 15-20 percent reduction in food intake and a significant reduction in weight gain. Importantly, metabolic¹⁶ disturbances¹⁷ associated with obesity, including hyperglycemia（高血糖） and deficient¹⁸ glucose¹⁹ metabolism²⁰, were greatly reduced by restoring the function of alpha2/delta-1," added Rios.

 

Some individuals who take gabapentin and pregabalin report weight gain. Both gabapentin and pregabalin are anticonvulsants, also used to treat nerve pain from, for example, shingles²¹ or diabetes. The findings from the Rios lab suggest that these drugs might contribute to weight gain by interfering²² with alpha2/delta-1 in the hypothalamus. This new understanding of alpha2/delta-1's role in appetite may allow researchers to develop complementary treatments that can prevent weight gain for patients taking these medications.

 

"We now know that alpha2/delta-1 plays a critical role in healthy BDNF function. The finding improves our understanding of the intricate neuroscience involved in appetite control. The next phase of our research will be to unravel²³ the mechanisms²⁴ mediating the satiety²⁵ effects of alpha2/delta-1 in the hypothalamus," said Rios.

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