Our brain represents only 2% of our weight. Paradoxically, it consumes 20% of our available energy. So it is relatively small but a very energetically expensive organ. The brain is a bit clumsy at storing energy, so the energy it uses is found circulating in the blood vessels (the glucose we obtain through food), so it needs constant irrigation. Most of this energy is consumed by neurons. This is surprising for a very simple reason: neurons do not have privileged access to blood glucose, since there is a barrier of astrocytes separating them. In other words, neurons are hungry for glucose but to obtain it they need to communicate with astrocytes to be able to work properly. This is basically what the lactate shuttle theory proposes. Who better to understand it than Luc Pellerin, one of its fathers?
Luc studied in Canada. He received his PhD in biochemistry from McGill University, specializing in neurochemistry. He did a postdoc at the University of Lausanne (Switzerland), in the department of physiology, joining Pierre Magistretti’s laboratory, where he was gradually promoted. He then became assistant professor, finally associate professor and head of the Department of Physiology. Two years ago, he accepted a position as professor of biochemistry and molecular biology at the University of Poitiers. And he will soon become director of unit U1313 at INSERM, where he will explore metabolic interactions in transplantation.
Juan García Ruiz: The brain consumes a large part of our available energy. How does it manage to obtain it?
Luc Pellerin: The classic version since the 1950s results from the work of Henry McIlwain, who showed that apart from glucose there were very few energy substrates that could fuel brain activity. Since then, several exceptions have emerged. Lactate has been shown to serve as a complementary energy substrate to glucose in certain situations. For example, immediately after birth, during intense exercise, during prolonged fasting or in pathological situations such as diabetes. Glucose itself remains the main substrate, but the idea that is beginning to emerge is that it is not always used directly as an energy source, but that there are metabolic exchanges between brain cells. This new hypothesis has been called the lactate shuttle and describes how some cell types, such as astrocytes, convert glucose into lactate, which is in turn transferred to other cell types such as neurons, capable of using it as a complementary energy substrate.
JGR: What is the ratio of glucose to lactate used by neurons as an energy source?
LP: The answer is still unclear. Early estimates suggested that neurons consume mainly glucose and relatively little lactate. Later in vitro experiments suggested that when a neuron is presented with lactate and glucose at the same time, about 75% of ATP production during oxidative phosphorylation comes from lactate and 25% from glucose. But this is under basal and in vitro conditions. During activation there is an increase in glucose consumption in astrocytes, much less in neurons. This points to the fact that when energy needs are higher, neurons are likely to use lactate preferentially. When we look at the distribution of energy consumption by the different cell types, neurons consume about half of the available glucose, which does not correspond to their high energy needs. This suggests that what is needed to fill the missing energy portion must come from another substrate such as lactate. One question that arises is related to the fate glucose: is it devoted entirely to support energetic activity or it can have other functions? And here again there is evidence suggesting that some of the glucose consumed is not metabolized in oxidative phosphorylation, but goes through the pentose pathway to regenerate NADPH. So there are other functions for which glucose is essential.
JGR: How would you explain from an adaptive point of view that neurons need to go through astrocytes to access energy? Wouldn’t it be much simpler for them to access it directly?
LP: This question arose relatively early on when the lactate shuttle hypothesis was proposed. The idea that neurons accessed glucose from the extracellular space was straightforward, so we used to think this was the case. Why bother having an intermediate like the astrocyte if the neuron can extract glucose directly? But if we consider that glucose can be used for other things and energy is obtained by other means, this implies that we are not dependent on a single substrate for everything. In this case, lactate could be used to produce energy, while glucose could be used to regenerate NADPH or synthesize neurotransmitters. The advantage is that the functions are decoupled and not solely dependent on one molecule. There are also advantages from a metabolic point of view. Lactate is converted to pyruvate and then goes directly to the Krebs cycle to produce ATP. In this case the neuron does not have to make any metabolic investment before going to the Krebs cycle to produce energy. In fact, the first step of glycolysis is glucose phosphorylation into glucose-6-phosphate via a hexokinase that requires ATP. So to recover energy from glucose, the neuron has to first invest some energy, which is a problem if it is already in a state of energy need.
The second problem is that glucose has to go through glycolysis before entering the Krebs cycle, and glycolysis is not a very rich ATP source. In other words, before reaching the step where we can produce a lot of energy (the Krebs cycle) there are a large number of steps (therefore a large investment of time) that makes it less efficient. Hence the advantage of having a faster energy source that does not require an initial energy investment. In addition, the astrocyte appears to be more oriented towards lactate production, whereas neuron gene expression is rather oxidative (energy consumption). Protein expression suggests that the coupling between the two processes is advantageous. Delegating glucose metabolism to the astrocyte seems to benefit the neuron, allowing it play other roles.
JGR: To what extent does the scientific community accept the lactate shuttle theory?
LP: When we proposed this hypothesis 25 years ago, we did not have a very warm welcome because we went against dogma. There were violent controversies, as happens with any emerging hypothesis. You need to bring new arguments and produce new data. Over time more and more scientists began to accept it. But there always remained a small nucleus of people who did not accept the hypothesis and tried to provide arguments to discredit it. I consider this to be a minority. I think that for most people in the field of metabolism or in the field of neuroimaging, this hypothesis is able to explain a great number of phenomena. But this questioning is actually a positive thing, because it pushes us to go further and to look for new evidence that allows us to better understand the phenomenon. The question is always the same: it is not a matter of finding out whether the lactate shuttle exists or not, but of understanding what really happens and how the brain uses its energy. At the moment it seems to be going in the direction of the lactate shuttle, but this theory could change.
JGR: What is your current research topic?
LP: We will soon publish an article in the journal PNS in which we provide evidence that inactivation of the transporters that enable lactate transport from the astrocyte to the neuron interfere with brain metabolic responses and with behavior (with learning and memory). So this phenomenon seems essential for specific brain functions. At first it was thought that glucose played a key role, now the focus shifts to lactate. The next step is to understand what is the role of glucose by using the same approach we used for lactate: what happens if we inactivate glucose transporters, for example, in neurons? Would we have the same effect as for lactate transporters? Probably both substrates (lactate and glucose) are essential but play different roles.
JGR: What approach do you use in your research?
LP: So far we have used two genetic approaches. On the one hand, we used viral vectors to reduce the expression of lactate transporters in rats, and on the other hand we have worked with transgenic mice in which we have selectively eliminated these transporters. In addition we do behavioral experiments, neuroimaging, and electrophysiology studies with Aude Panatier.
JGR: What do we still do not know?
LP: There is something that remains unclear. We know that lactate is a good neuronal energy substrate. It is taken up by neurons through a transporter called monocarboxylate transporter type 2 (MCT-2), which is expressed on the surface of the plasma membrane. It has been shown that MCT-2 is also found in synapses, specifically in the postsynaptic component. This is curious: since it is the transporter of an energy substrate, why is it there? Is there a specific energy requirement at the synapse?
Secondly, it has been shown that this transporter can associate with AMPA glutamatergic receptors (GluA2 subunits) in the postsynaptic membrane. This raises another question: in addition to being an energy transporter, can it regulate synaptic transmission? Are these two functions linked? There are other unresolved questions. For example, what regulates the expression of lactate transporters in astrocytes? This has already been studied in neurons, where it is translationally regulated by trophic factors such as BDNF (editor’s note: brain-derived neurotrophic factor). But in the astrocyte it has not been investigated. Is the expression related to synaptic plasticity? What are the signals involved? As you can see, there are still many unknowns. And the ideal would be to be able to translate all this to humans, to look for possible therapeutic approaches.
JGR: What led you to research?
LP: I have been interested in research since I was very young, since I was about twelve years old. And not because there were researchers in my family environment. I was always attracted to the idea of exploring something unknown. I quickly gravitated towards science, and when the time came to make a choice at university, I went for biochemistry. What really appealed to me was investigating the unknown and thinking that maybe I would come up with some answers.
JGR: What have you learned from your years of experience in science?
LP: Scientific training gives a Newtonian vision of things: there are rules and laws, and by applying them, we can make discoveries. With experience I realized that, although this is very useful, in the end the world is not so predictable and that there is a part of imponderable, of imagination, something that appeals more to intuition and creative sense. I have learned to develop these aspects and not to limit myself to the purely rational, but to leave room for imagination, for freedom of thought. Sometimes solutions to problems do not emerge from a purely rational approach because there are many parameters that we do not control.
I have also realized that there are multiple ways of looking at the world and that all of them can contribute to our understanding. I will share with you a little anecdote. When I started my postdoc, I worked with a Chinese doctoral student. It was very difficult for me to understand his reasoning, but in the end we always came to the same conclusion. His approach was completely different, but we always arrived at the same result. You have to take all this into account. Sometimes, only with different points of view can we find the solution to a problem that is not possible to solve with our own way of seeing things. I try to foster this vision in my team, which has people from very different backgrounds to avoid the in-breeding that makes everyone think the same way.
JGR: How do you see research in Europe compared with USA and Canada?
LP: In Canada, the size of research is still relatively small compared to USA. So we always keep our eyes on what is happening in the United States. But I did my thesis in Montreal, in an English-speaking university, and it was like a continuity of what was going on in the United States. So when I talk about North American research, I don’t really differentiate between Canadian and American culture. But there is a big difference between North American and European one, which actually led me to do my postdoc in Europe. In North America, research is very results-directed. The notion of efficiency is always present. This introduces extremely high pressure, because not only do you have to find the funds for research, but you also have to produce. Although it has its advantages, one should not forget its disadvantages. One of them is that the time for reflection becomes too short. We come up with short-term strategies to avoid starting projects that do not produce results quickly. When I came to Europe 25 years ago, I saw something different. I had longer periods of reflection, and although productivity was lower, I could aspire to have a greater scope. This vision of Europe is slowly disappearing. But that vision is perhaps what allowed me to propose the lactate shuttle hypothesis. All the work necessary to develop the hypothesis and reproduce the experiments, and which allowed us to publish in major journals, spanned decades. This would not have been possible in any other context. The North American phenomenon of efficiency, productivity and profitability is reaching Europe, which means that long-term research is disappearing. We have less and less time, and we cannot afford a project that takes 4 to 8 years to produce its first results. We have to adapt to this new way of working, but I deplore it a bit. The ideal would be to keep the best of both worlds. What I did not like about Europe was that there was a lot of waste and little efficiency. Now we gain in efficiency but lose in long-term thinking.
JGR: What would you tell to young researchers to encourage them to do research?
LP: You may not like my answer. In research many young people are solicited, but in the end very few are chosen. If you are not clear about that, maybe it is better to forget about it. If you start to doubt yourself, think it’s not for you or you’re not ready to make the effort, maybe it’s not for you. It has to be a passion. You have to be convinced that this is what motivates you, what makes you get up in the morning, what makes you want to go back to the lab even if sometimes you get discouraged. When you are really convinced that this is what you want to do, go for it. But the conditions are so difficult and the rewards so few that there is no point in pursuing this kind of career if you are not completely sure. You have to be aware of the reality of things and I don’t want to take anyone for a ride. When you are sure, what you need is to find mentors, people who will support you and who can help you in the most difficult stages. Research is an interconnected field, a system in which you need to build your own network.
JGR: Would you recommend a scientific book that left a mark on you?
LP: I am going to recommend a book entitled Discovering, written by Robert Scott Root-Bernstein. It was given to me as a gift by a friend who was doing her thesis when I was defending mine, just before doing my postdoc. It’s a reflection on what makes some scientists make discoveries and others don’t. What is the role of education, the way one is trained or the approach to science, in success? There was a chapter on affiliation. If you look at Nobel Prize winners, there are often connections. People who come from the same laboratory pass on their knowledge to others, and then to others, and so on. The idea is that there is a certain way of conceiving scientific research. And since this vision is passed on from generation to generation in the same laboratory, this predisposes them to have a higher probability of making an important discovery. He also explains that among the Nobel laureates, many people had other passions besides science. For example, there are many musicians.
JGR: would you like to share a message with the readers?
LP: The important thing, in my opinion, is to enjoy science all the time. It is a difficult career. Don’t expect recognition from your environment, from your academic environment, from your hierarchy. Your reward should come from the pleasure you get from doing what you do. This has been my leitmotiv from the beginning. I had been hoping for a long time that at some point there would be recognition from my colleagues, but I realized that it doesn’t work that way. It would be a shame to sacrifice your whole career trying to get this prestige, knowing that it may never happen, and that you’ve really sacrificed and put in a lot of time and not really enjoyed it. The idea is that you have to have fun doing research, really do what interests you, and not do it because others ask you to or because you want to please those who fund you. Pursue your interests, pursue what motivates you.