Metabolic defects in mice corrected with transplanted embryonic neurons

A new study has revealed that immature neurons taken from healthy mouse embryos can repair damaged brain circuitry and partially normalize metabolism when transplanted into adult mice that have grown morbidly obese due to a genetic deficiency. This proof-of-principle discovery represents one step down a long road toward neuronal replacement therapy, which researchers hope might one day be used to repair brains that have been injured by trauma or disease.

Artur Czupryn and colleagues took the immature neurons from the hypothalamus of wild-type mouse embryos and transplanted them into the hypothalamus of adult mice lacking a receptor for the hormone, leptin, which is known to regulate body weight. The researchers observed that the donor neurons were able to differentiate into four distinct neuronal types that then formed functional connections in the brains of the obese mice.

Their study appears in the 25 November 2011 issue of the journal Science, which is published by AAAS, the nonprofit science society.

"We chose this problem not because, even for a moment, we would pursue the idea of neuron transplantation for the treatment of obesity," explained Jeffrey Macklis from Harvard University, a corresponding author of the report. "What we did was take this very complicated circuitry in the hypothalamus that has a very clear, measurable outcome—not only obesity in the mice, but changes in their serum glucose (like diabetic human beings have), changes in their insulin levels and changes in their fat vs. lean body weights—and we used that complex circuitry as a test case for whether precisely selected and controlled neuron transplants could really rewire the brain."

The transplanted neurons did apparently restore leptin signaling in the brains of the obese mice because the rodents slimmed down and their metabolism began returning to normal levels, according to Czupryn and his colleagues.

"What we found is that these neurons not only turned into the right kinds of cells, but that they sent signals to the recipients' brain and received signals from the recipients' brain," said Macklis.

Although the researchers say that neuronal replacement is certainly not a practical approach to treating obesity, their study nonetheless provides evidence that the transplantation of donor neurons at the appropriate stage of development can promote functional recovery of a brain region that controls a complex phenotype.

This report by Czupryn et al. was funded by the National Institutes of Health, the Jane and Lee Seidman Fund for Central Nervous System Research, the Emily and Robert Pearlstein Fund for Nervous System Repair, the Picower Foundation, the National Institute of Neurological Disorders and Stroke (NINDS), the Nancy Lurie Marks Family Foundation, the Polish Ministry of Science and Higher Education and the Foundation for Polish Science.

The American Association for the Advancement of Science (AAAS) is the world’s largest general scientific society, and publisher of the journal, Science (www.sciencemag.org) as well as Science Translational Medicine (www.sciencetranslationalmedicine.org) and Science Signaling (www.sciencesignaling.org). AAAS was founded in 1848, and includes some 262 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of 1 million. The non-profit AAAS (www.aaas.org) is open to all and fulfills its mission to “advance science and serve society” through initiatives in science policy; international programs; science education; and more. For the latest research news, log onto EurekAlert!, www.eurekalert.org, the premier science-news Web site, a service of AAAS.