“Our new study has identified novel populations of nerve cells that regulate appetite, thermogenesis and physical activity,” said TSRI Professor Baoji Xu, who led the research. “We think these neurons could be targets for drug development.”
The findings were published by the journal Cell Metabolism online ahead of print on June 11.
In the new study, Xu and his colleagues examined several groups of neurons that express a substance called “brain-derived neurotrophic factor” (BDNF) within a small brain region called the paraventricular hypothalamus.
BDNF is an extremely important protein in the brain and is involved in a number of functions. It has been shown that deleting the BDNF gene causes significant problems, among them, dramatically increased appetite (hyperphagia) and severe obesity.
The new study shows that deleting the BDNF gene also impairs thermogenesis—the ability of cells to burn fat to produce heat. The study further reveals two distinct types of BDNF neurons—those that control appetite or satiety and those that control thermogenesis. Not only do these two groups play different biological roles, they are located in two separate sections of the paraventricular hypothalamus brain region.
This “geographical” split raises some interesting questions. “We don’t yet know what the distinctive placement means to the control of body weight, nor do we know if these two clusters of neurons communicate with each other as yet,” said Juanji An, the first author of the study and a member of the Xu lab. “But given the fact that mice and humans with mutations in the BDNF gene or its receptor develop severe obesity, a better understanding of the mechanism underlying the effect BDNF has on body weight could provide great insights into the regulation of energy balance.”
Xu is also hopeful about the potential of BDNF as a drug target. “Our findings suggest that activation of each of these two populations of neurons should powerfully suppress appetite or promote energy expenditure,” he said. However, he cautions that because BDNF’s functions are so widespread, a good drug candidate would need to closely target only BDNF-expressing neurons in the paraventricular hypothalamus, thus limiting potential side effects.
In addition to Xu and An, other authors of the study, “Discrete BDNF Neurons in the Paraventricular Hypothalamus Control Feeding and Energy Expenditure,” include Guey-Ying Liao and Clint E. Kinney of TSRI, and Niaz Sahibzada of the Georgetown University Medical Center. See http://www.cell.com/cell-metabolism/home
The work was supported by grants from the National Institutes of Health (DK089237 and DK103335) and the Klarman Foundation.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates—work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
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