Pharmacological and genetic ablation of NG2-glia, but not microglia, leads to obesity •NG2-glial ablation causes LepR processes in the median eminence to degenerate •Arcuate nucleus LepR neurons lose responsiveness to leptin after NG2-glia ablation •X-irradiation aimed at the median eminence is sufficient for weight gain induction
Discovery opens door to development of new drugs to control weight gain and obesity. 4 years ago, Kokoeva and her team set out to explore which brain cells might play a role in the process of leptin sensing and weight gain. The answer, it turns out, lies in the median eminence, a brain structure at the base of the hypothalamus.
The McGill team has now discovered that without NG2-glia cells in place in the median eminence, the leptin receptors in the brain never receive the messages from the body telling it that it is sated. “Most of the brain is a well-protected fortress, designed to shelter delicate nerve cells,” says Kokoeva. “The median eminence is outside these protections, and so can be a dangerous environment for the nerve cells that detect leptin. We think that the NG2-glia cells act to support and shelter the leptin receptor neurons, enabling them to instruct the body when to stop eating.”
“We developed an interest in NG2-glia cells in this specific part of the brain because unlike neurons, during much of our adult lives these cells are constantly dividing and they do so most actively in the median eminence,” says Tina Djogo. Because of their particularly high turnover in the median eminence, they wondered if the NG2-glia cells might play a role in leptin sensing and therefore in appetite control. So they used a drug to kill the NG2-glia cells in the median eminence of a group of mice and then watched to see whether there was a difference in food intake. The results were stunning.
Within 3 days after they started to receive the medication, some of the mice dubbed “gainers” had already started to eat more vs control group of mice who had not received medication. And by 30 days afterwards, the weight of some of the mice had doubled – from 25 to ~50 grams. “But what was most exciting to us, was that even though NG2-glia are found across the brain” explains Sarah Robins, “it was only when we removed these cells from the median eminence that we saw this clear increase in body weight.”
“People who have been treated for brain tumours using radiation to block cell proliferation often become overweight,” says Kokoeva. “However, there has never been any satisfactory explanation, but our experiments in mice now suggests that the reason for this weight gain may be the loss of NG2-glia in the median eminence as a result of radiation.”
They are hopeful that the identification of NG2-glia in the median eminence as crucial elements in body weight and appetite control will pave the way to new targeted anti-obesity approaches directed towards maintaining or raising the NG2-glia population in the median eminence. https://www.mcgill.ca/newsroom/channels/news/brain-cells-aid-appetite-control-identified-260810
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