Why is the brain dependent on glucose?

Question

The strict dependence of the (human) brain on glucose has always been puzzling to me. While ketones can substitute for a portion of the brain's energy needs, it cannot substitute completely: blood glucose levels below 2--3mM somewhere causes serious neurological problems and can lead to unconsciousness.

Other body tissues are not strictly dependent on glucose, but can oxidize amino acids as well, which is a good backup solution since there is always lots of protein around. But not the brain.

In terms of evolution, this strict glucose dependence must be a major drawback --- falling unconscious just because you don't get enough sugar is probably a bad thing out in the wilderness, when the lions are after you ... So there must be a very important reason.

So why is the brain so dependent on glucose?

Answer 1

I want to present another (possibly more practical) approach towards this phenomenon. Lets begin with amino acids as alternatives.

1. Amino acids, apart from being a source of toxic ammonia, are also harmful to the brain in another way. The two (concerned) types of amino acids, aromatic and acidic ones, are a lot more than just energy sources for the brain. Aromatic amino acids: tyrosine, phenylalanine and tryptophan, are precursors for the biosynthesis of neurotransmitters like serotonin, melatonin, norepinephrine, dopamine, etc. The greater the amount of precursors, more the product formed. Talking about acidic amino acids, glutamate and aspartate are themselves neurotransmitters. So, same case could apply to them too. So, it might have been that neurons, in evolution, decided to just get rid of such sensitive and powerful energy sources which can disrupt their basic function. You can see Fernstrom, 1994 for a study on this.

2. Fatty acids are definitely a nice candidate. But they have some side effects too. For a long time, it was thought that since fatty acids (or lipids in general) are attached to albumin while in blood, they cannot cross the blood-brain barrier (see Stryer for example). But, this is not the case, as now proven. Then why are fatty acids not a preferred energy source for brain? There might be quite a few reasons for this.

   • First, $\beta$-oxidation of fatty acids demands more oxygen as compared to glucose, making neurons more vulnerable to hypoxia. For example, the reaction for complete oxidation of glucose is (from Molecular Cell Biology):

   $\ce{C_6H_{12}O_6 + 6 O_2 + 36 ADP^{3-} + 36 P_i^{2-} + 36 H^+ \rightarrow 6 CO_2 + 36 ATP^{4-} + 42 H_2O}$

   On the other hand, the reaction for $\beta$-oxidation of palmitic acid is (from pharmaxchange):

   $\ce{C_{37}H_{66}N_7O_{17}P_3S (Palmitoyl-coA) + 23 O_2 + 108 P_i^{2-} + 108 ADP^{3-} \rightarrow C_{21}H_{36}N_7O_{16}P_3S (coenzyme-A) + 108 ATP^{4-} + 16 CO_2 + 23 H_2O}$

   where palmitic acid is $\ce{C_{16}H_{32}O_2}$. This clearly shows that glucose oxidation requires less oxygen (1 molecule per carbon) as compared to fatty acids (almost 3 molecules per 2 carbon).

   • Second, nonesterified fatty acids (NEFA) decrease membrane potential at inner mitochondrial membrane, causing collapse of electrochemical proton gradient.

   • NEFA also interfere with electron transport chain, stimulating generation of reactive oxygen species like superoxide ions (see Zhang et al, 2006 for example).

   • Apart from this, the rate of ATP generation from fatty acids is slower as compared to glucose, which makes glucose a better option for neurons (see Stryer).

   

   All these factors might have a played a role in making neurons choosy for glucose. This is also supported by the fact that one of the enzymes of $\beta$-oxidation, 3-ketoacyl coenzyme-A thiolase, has significantly lower activity in neurons as compared to other tissues (Yang et al, 1987). You can see Reiser et al, 2013 for a study on this.

PS: It has been shown that the brain can also use lactate along with ketone bodies as an energy source. See Wyss et al, 2011 to know more about this.

Answer 2

Glucose is the only fuel normally used by brain cells. Because neurons cannot store glucose, they depend on the bloodstream to deliver a constant supply of this fuel. Fatty acids do not serve as fuel for the brain, because they are bound to albumin in plasma and so do not traverse the blood-brain barrier. In starvation, ketone bodies generated by the liver partly replace glucose as fuel for the brain. (Biochemistry. 5th edition.Berg JM, Tymoczko JL, Stryer L.)

Also, amino acid catabolism is the process of using amino acids as an energy source. Turning amino acids into molecules that can be used in the Krebs cycle takes energy, which means that burning protein for fuel is not as efficient as burning carbohydrates. In addition, your body needs amino acids to make new proteins. When amino acids are used as an energy source, it reduces the reserves of amino acids that are available for protein synthesis.

Answer 3

This is something I have been researching on and off for many years. I studied nutrition back in the early 1980s and our lecturer always said that "fats burn in the flame of CHOs". He said that the citric acid cycle was dependent on oxaloacetic acid - the predominant source was from glucose (pyruvic acid). https://www.sciencedirect.com/topics/medicine-and-dentistry/oxaloacetic-acid

In nutrition, for patients with epilepsy, they are given a ketogenic diet as this is known to suppress brain signals. Clearly the brain functions sub-optimally when deprived of glucose. One of my concerns with the rise in dementia is the high protein/low carb diet proposed, and the claims that the body (and brain) can do without CHOs.

The other piece of research was from Professor Robert Horn (retired, Oslo) in his work for students. He compiled a wonderful PDF on glucose metabolism and here I quote: "The blood-brain-barrier is comprised of glia cells, primarily astrocytes. A small fraction of the glucose released from capillaries wanders directly to nerves and synapses. However, most is "trapped" in astrocytes and oxidized to lactate by these cells. Lactate goes further into the brain and nourishes the brain's neurons. This seems to be especially important for glutamatergic neurons which comprise much of the brain. The astrocytes also efficiently pick up released glutamate, convert this to glutamine, and send the product back to glutamatergic neurons where it continues to cycle as a neurotransmitter. The axons do not contain glycogen and are, therefore, completely dependent upon the lactate sent from astrocytes to maintain ATP levels. Astrocytes and other glia cells appear to have some glycogen which can serve as a very short-term source of lactate.So the answer to the preceding question is that much of the brain is dependent upon lactate from glia cells to provide substrate for aerobic energy production; ketone bodies cannot cover their substrate requirements. One can reduce glucose consumption and use ketone bodies during starvation. However, some neurons must have lactate and the brain must continue to use blood sugar."

Answer 4

The body uses 2 dedicated groups of fuel molecules (fats and sugars) and can break down its own structure molecules in case of emergency (proteins). The brain uses sugars, mostly glucose, and ketone bodies, a soluble form of acetyl derived from fat breakdown. I love this question, Roland, since you've probably hit on an open, poorly investigated question that goes to the fundamentals of why neurons evolved to be this specialized. So why does the neuron rely much less on fats and proteins than more flexible cells like those of the liver?

Protein digestion could indeed be dangerous for neurons because it produces ammonium (NH4+). Neither fats nor sugars contain significant amounts of nitrogen. Their final breakdown products, H2O and CO2, are harmless. Ammonium, on the other hand, is very similar to potassium (K+), an ion central to the neuronal membrane potential and thus its function. It has a similar size and charge (see image below) and is hypothesized to mess with potassium signaling in the brain. It might do this by interfering with K+ transporters (see this schematic by Eid).

This leaves us with fats. I have 2 hypotheses here. The final steps of fat breakdown in the mitochondrion involve the transfer of electrons onto oxygen to produce water. An unavoidable side reaction here is the creation of a small amounts of reactive oxygen species that have the potential to damage close-by molecules via radical reactions. Since neurons are so long lived, this is very dangerous for them as they accumulate damage little by little. Not so for liver cells which are readily replaced if damaged beyond recovery. Second, fat breakdown is a much slower way to energy/ATP than glucose breakdown, since it involves the sequential shortening of the fatty acid chain (beta oxidation), the generation of reduced intermediates (mostly NADH in the citrate cycle), and finally oxidative phosphorylation - several dozen steps in total. Glucose metabolism yields ATP quickly in just a few steps (glycolysis). Ketone bodies also fit, since they are already very short and thus much more quickly metabolized than long chain fatty acids. A combination of these 2 reasons might be why neurons prefer glucose to fats, but I believe this is a poorly investigated question that merits more research. PhD anybody?