The Impact of the Ketogenic Diet on Glial Cells Morphology. A Quantitative Morphological Analysis

Kinga Gzielo, Zbigniew Soltys, Zeon Rajfur, Zuzanna Setkowicz

Neuroscience, available online 18 June 2019

https://doi.org/10.1016/j.neuroscience.2019.06.009

Abstract

The ketogenic diet is reported to protect against cognitive decline, drug-resistant epilepsy, Alzheimer’s Disease, damaging effect of ischemic stroke and many neurological diseases. Despite mounting evidence that this dietary treatment works, the exact mechanism of its protective activity is largely unknown. Ketogenic diet acts systemically, not only changing GABA signalling in neurons, but also influencing the reliance on mitochondrial respiration, known to be disrupted in many neurological diseases. Normally, the human body is driven by glucose while ketogenic diet mimics starvation and energy required for proper functioning comes from fatty acids oxidation. In the brain, astrocytes are believed to be the sole neural cells capable of fatty oxidation. Here we try to explain that not exclusively neurons, but also morphological changes of astroglia and/or microglia due to different metabolic state are important for the mechanism underlying the protective role of ketogenic diet. By quantifying different parameters describing cellular morphology like ramification index or fractal dimension and using Principal Component Analysis to discover the regularities between them, we demonstrate that in normal adult rat brain, ketogenic diet itself is able to change glial morphology, indicating an important role of these underappreciated cells in the brain metabolism.¹

Comment

Keto-diets are known to help protect against cognitive decline, epilepsy, and neurodegenerative disorders like Alzheimer’s disease and Parkinson’s disease, and could help to improve aspects of mental function.

Many mechanisms are suggested for this, including improved fuelling for the brain (especially if damaged) by the ketone beta-hydroxybutyrate (BOHB), increased adenosine in the brain (a ‘relaxing’ neurotransmitter), improved GABA-glutamate ratios (which help to reduce over-excitation of neurons and reduces neurone damage) and increased regeneration and repair of neurons, along with reducing inflammation.

It’s likely that these effects work together and that there is no one ‘answer’ as to the question of why ketogenic diets and ketones are proving so beneficial for brain health in emerging research.

In this study, the Polish research team looked specifically at the effect of effects of a ketogenic diet on astrocytes, a type of glial cell in the brain. Astrocytes are named due to their star-shaped structure (Astro = star, cyte refers to cell) and makeup around 20-40% of glial cells. Glial cells themselves are non-neuronal cells (i.e. they are not neurones and do not transmit messages in the brain and nervous system) that help to support neurons in a number of ways including:

• Regulating fluid balance in the brain (supporting extra-cellular fluid)
• Regulating repair of neurones (some increase repair, some decrease it)
• Creating the myelin sheath around cells which acts as an insulator and allows proper nerve transmission (think of it as the plastic around copper wiring)
• Clearance of glutamate and other toxic neurotransmitters, after they have played their roles, from the synapse (the junction between neurones)

What was shown in this study?

The study ran for 4 months and included 8 mice. The major finding was that astrocytes in the keto-diet brains were more diverse and complex than those in the control diet group.

The major finding was that astrocytes in the keto-diet brains were more diverse and complex than those in the control diet group

What are some challenges to the findings?

Mice are notoriously poor ketogenic subjects. They achieve ketosis far less easily than humans and respond differently to ketogenic diets. In particular, they are more likely to gain weight and fat on a ketogenic diet than humans, who almost universally lose fat and weight on a keto-diet (and more so than if following a eucaloric higher-carb diet). However, the structures of the brain are very similar between different mammals.

What does this all mean?

Glial cells are key supporting cells for neurones of the brain (as mentioned previously) and are involved in maintaining glucose homeostasis in the brain, sensing insulin and leptin levels, and can produce ketones for use by neighbouring neurones.

A change in ‘morphology’ (structure) does not always imply benefit. While in this study there were clear differences in the complexity and diversity of glia astrocytes, that does not necessarily confer benefit. However, in this study, it does seem that these changes in structure are positive and are one of the many reasons why a ketogenic diet encourages health benefits to the brain and nervous system.

Along with the other plausible mechanisms by which ketogenic diets are thought to improve brain health and function, and the functional results (improved outcomes) being demonstrated for this in human research, the change in structure of glial cells elicited by a keto-diet is likely to be one of the mechanisms by which health can be improved by a keto-diet.

the change in structure of glial cells elicited by a keto-diet is likely to be one of the mechanisms by which health can be improved by a keto-diet

References

1.            Gzielo K, Soltys Z, Rajfur Z, Setkowicz ZK. The Impact of the Ketogenic Diet on Glial Cells Morphology. A Quantitative Morphological Analysis. Neuroscience. 2019.