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Neuroscience Study Uncovers New Player in Obesity

A Protein Directs Appetite Suppressor in the Brain; Implications for Obesity Treatment

January 7, 2014

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Siobhan Gallagher siobhan.gallagher@tufts.edu 617.636.6586

BOSTON (January 7, 2014, 5:00 pm ET) — A new neuroscience study sheds light on the
biological underpinnings of obesity. 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 intake 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 and other conditions that interfere with this protein,
such as gabapentin and pregabalin, can cause weight gain.
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The protein – alpha2/delta-1 – has not been linked previously 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 Print Email
neurotrophic factor (BDNF). A previous study by Rios determined that BDNF plays a critical role in
appetite suppression, while the current study identifies a central mechanism mediating the inhibitory
effects of BDNF on overeating.

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 “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 cellular and molecular physiology and neuroscience program
faculties 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 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.

“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.

Additional authors on the new study are Jennifer A. Felsted, a graduate student in biochemical and molecular nutrition at the Friedman School
of Nutrition Science and Policy at Tufts University and a member of the Rios lab; Sarah Teillon, Ph.D., a graduate of the Sackler School and

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 former member of the Rios lab; Shabrine Daftary, Ph.D., a research associate in the Rios lab; Micaella Panessiti, a neuroscience Ph.D. student
at the Sackler School and member of the Rios lab; and Jena Wirth and Miguel Sena-Esteves, Ph.D., associate professor, both of the department
of neurology and gene therapy center at the University of Massachusetts Medical School.

Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National
Institutes of Health under award number R01DK073311; and the American Heart Association. Joshua W. Cordeira and Sarah Teillon were
supported by a training grant under award number T32DK07542; Jennifer A. Felsted was supported by a training grant under award number
T32DK062032, all from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

Cordeira JW, Felsted JA, Teillon S, Daftary S, Panessiti M, Wirth J, Sena-Esteves M, Rios M. The Journal of Neuroscience. “Hypothalamic
dysfunction of the thrombospondin receptor α2δ-1 underlies the overeating and obesity triggered by BDNF deficiency.” Published January 8,
2014 DOI:10.1523/JNEUROSCI.1572-13.2014

About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences
Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in
innovative medical and population health education and advanced research. Tufts University School of Medicine emphasizes rigorous
fundamentals in a dynamic learning environment to educate physicians, scientists, and public health professionals to become leaders in their
fields. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, the biomedical sciences,
and public health, as well as for innovative research at the cellular, molecular, and population health level. Ranked among the top in the nation,
the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of
Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its effect on the advancement
of medical and prevention science.

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Related Links
Overeating and Obesity Triggered by Lack of BDNF

Journal of Neuroscience: Hypothalamic Dysfunction of the Thrombospondin Receptor α2δ-1 Underlies the Overeating and Obesity...

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