Twenty-years ago there was a big step forward in the understanding of obesity when researchers discovered that a person’s appetite is controlled by a key molecule called leptin. Leptin is a hormone produced by fat cells which is delivered by the blood to the brain, to signal that the person is full and can stop eating. However, even though receptors for leptin were discovered soon after in the hypothalamus, a brain area that regulates food intake and body weight, it has remained unclear how exactly leptin is detected. Now, a study from researchers at McGill University shows that without a particular group of cells, known as NG2-glia cells, in the median eminence, the leptin receptors in the brain never receive the messages from the gut. The team state that their findings suggest that the NG2-glia cells act to support and shelter the leptin receptor neurons, enabling them to instruct the body when to stop eating. The opensource study is published in the journal Cell Metabolism.
Previous studies show that NG2-glia represent a major glia-cell class known for their role as precursors to oligodendrocytes. Despite their dense presence throughout the CNS, including the hypothalamus, their physiological significance in the adult brain has only recently begun to be explored. The median eminence is a brain structure at the base of the hypothalamus. Likened to a busy hub or market place, it enables hormones and molecules of various kinds to travel in both directions between the brain and the bloodstream to ensure that the bodily functions work smoothly. Due to the particularly high turnover of NG2-glia in the median eminence, the lab hypothesized NG2-glia cells might play a role in leptin sensing and therefore in appetite control. The current study shows that ablation of NG2-glia, but not microglia, in the median eminence leads to selective degeneration of leptin receptor dendrites in the arcuate nucleus, causing primary leptin resistance and obesity.
The current study used a drug to kill the NG2-glia cells in the median eminence of a mouse-model to show there was a difference in food intake. Results show that within three-days after they started to receive the medication, some of the mice dubbed ‘gainers’ had already started to eat more compared to the control group. Data findings show that by 30-days, the weight of some of the mice had doubled, from 25 grams to approximately 50 grams.
The group then corroborated the role of the NG2-glia cells in the median eminence in appetite control through experiments using genetically modified mice and irradiation. The researchers state that this latter discovery suggests an explanation for the previously unexplained phenomenon in human brain cancer survivors. They go on to add that people who have been treated for brain tumours using radiation often become overweight, however, there has never been any satisfactory explanation; their findings in mice now suggest that the reason for this weight gain could be the loss of NG2-glia in the median eminence as a result of radiation.
The team surmise that their findings show pharmacological and genetic ablation of NG2-glia, but not microglia, leads to obesity. They go on to add that NG2-glial ablation causing leptin receptor processes in the median eminence to degenerate and arcuate nucleus leptin receptor neurons to lose responsiveness to leptin; with irradiation aimed at the median eminence also shown to cause weight gain. For the future, the researchers state that 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.
Source: McGill University
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