Cannibal neurons

A recent study published this month in Cell Metabolism indicates for the first time that the brain, in specific situations, may actually eat itself. Researchers from the Albert Einstein College of Medicine discovered that a starvation state causes cells in the hypothalamus to commit autophagy, the breakdown, consumption and recycling of itself by the cell's lysosomes. This process is common in cells throughout the body and is an efficient method of energy conservation. The cell partitions off extraneous parts of itself from the core of the cell body and these bits are then broken down by the lysosomes; the resulting release of nutrients are consumed by the remaining cell in order to maintain survival. Autophagy is a natural process in the cycle of cell growth and death, and is increased during starvation to provide an alternative source of nutrients and energy when external resources are not readily available. However, it was previously thought that the brain was exempt from this cannibalistic process during nutrient deprivation. To examine this process in neurons, researchers first simulated starvation in hypothalamic cells by withholding a nutrient serum. After just 1 hour, these cells began to produce LC3-II, an indicator that autophagy was taking place. The levels of LC3-II progressively increased as the time without serum continued, however this process was reversed once the cells were provided with nutrients. Researchers then repeated these results in vivo in starved rats. Rats who had been fasted for 12 hours showed increased autophagy in the hypothalamus via elevated LC3-II levels in these neurons, compared to groups of both satiated and previously starved but recently re-fed rats who showed little to no change in the autophagic marker. After repeating the experiment in other neurons from different areas of the brain, coupled with the lack of findings from previous studies of autophagy in neurons, scientists have tentatively concluded that the hypothalamus is the only region in which this process occurs.

The wider implications of these results have to do with the specific region in which they are seen. The hypothalamus is a major regulatory center of the brain involved in hormone and neuropeptide release, which in turn control the homeostatic regulation of metabolism, hunger and satiety, among others. However, when these hypothalamic cells are broken down by starvation-induced autophagy, the gentle balance of these regulatory hormones is up-ended. Nutrient deprivation and autophagy can result in an increase in free fatty acid production in the liver, which in turn elevates hypothalamic levels of the peptide AgRP, involved in increased food intake. Thus, when an individual is able to eat again, they are more likely to consume greater quantities of food than normal. These findings were further supported by studying mice who had been genetically modified to produce AgRP, but not be susceptible to autophagy. Compared to normal mice, these genetically modified mice, when starved, did not have elevated AgRP levels, nor did they demonstrate the binge eating that is common after long fasts, and consequently they also had lower body weight and body fat than normal control mice.

The implications of these results in weight loss and dieting further support the idea that fasting or extreme low-calorie diets are only beneficial in immediate weight loss, but can have substantial contradictory results in the long term. It is widely accepted that food deprivation causes one to feel hungry and irritable, but the notion that diets can lead to brain cell loss, resulting in a greater inability to manage what one eats, is a novel theory. This can lead to loss of control, binges, regret, and further self-imposed starvation that is often seen in the vicious cycle of extreme dieting. Additionally, the increase in fatty acids during autophagy can also occur after an increase in fat consumption. Therefore, not only starvation, but also the following binges on fatty foods can result in an increase in the desire and consumption of food. To avoid this counter-productive weight loss tactic, it is recommended to instead change the source of your diet (i.e. from high fat foods to fruits and vegetables) and only decrease calorie intake in moderation, while still ensuring your body receives the nutrients and energy it needs.

Dana Smith

PhD student in Experimental Psychology at the University of Cambridge