An in vivo study reveals how a protein in the brain, alpha2/delta-1, helps regulate food intake and body weight and may help explain why medications that are prescribed for epilepsy and other conditions that interfere with this protein, such as gabapentin and pregabalin, can cause weight gain.

The alpha2/delta-1 protein has not been linked previously to obesity but the team led by Maribel Rios, Ph.D., associate professor in the department of neuroscience at Tufts University School of Medicine, found that alpha2/delta-1 facilitates the function of another protein called brain-derived neurotrophic factor (BDNF).  

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 inhibited 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 mitigated. In addition, blood sugar levels (related to diabetes in humans) were normalized.

A protein previously unrelated to obesity has been linked in a new in vivo study. Credit: CDC/Debora Cartagena

"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 obese mice lacking BDNF in the brain, we saw a 15-20 percent reduction in food intake and a significant reduction in weight gain. Importantly, metabolic disturbances associated with obesity, including hyperglycemia and deficient glucose metabolism, 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, shingles or diabetes. The findings from the Rios lab suggest that these drugs might contribute to weight gain by interfering 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 unravel the mechanisms mediating the satiety effects of alpha2/delta-1 in the hypothalamus," said Rios.

This latest finding builds on Rios's previous studies of BDNF and its role in regulating body weight. Earlier work by Rios established BDNF as an essential component of the neural circuits governing body weight in adult mice. Rios also determined that BDNF expression in two regions of the brain is required to suppress appetite.