Lactate and ketone metabolism in context of brain energetics and lactate shuttle | Peter Attia
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Astrocytes, star-shaped cells found in the brain and spinal cord, use glucose to generate lactate, which is then utilized by neurons. In addition, exercise preferentially causes the brain to take up lactate. Dr. Attia discusses some interesting research from several decades ago that uncovered the shifts in metabolism that occur in the human body and brain upon extreme fasting. In this clip, Dr. Peter Attia and Dr. Rhonda Patrick examine the use of various fuel sources in brain metabolism.
Rhonda: When you're talking about diabetes in the brain being Alzheimer's, what's really interesting to me is the fact that neurons are actually mostly using lactate from astrocytes. Astrocytes are glycolytic. The astrocytes are these brain cells in your brain which are using glucose mostly, or using glucose to generate lactate. Lactate then gets shuttled into neurons, and the reason why neurons like that is because it's thermodynamically favorable, much like beta-hydroxybutyrate which you mentioned, BHB, because it can shunt right into the TCA cycle in the mitochondria...
Peter: But wait, how does the brain outcompete the liver for lactate? So, like, if I made you go out there and do a bunch of burpies, right? So the...I'm blanking on the name of the transporter.
Rhonda: MCT.
Peter: MCT1 or MCT2? Which one is the transporter out of the muscle?
Rhonda: I don't know which one.
Peter: Okay, but the majority lactate is going to be generated in the muscle. So then MCT is going to transport that out. And remember, it's going to go through the portal system...it actually it doesn't go to the portal, it passes through the cava, but it's still passing through the liver. How does the brain managed to get any without the liver taking it all into the Cori cycle, which seems to me the preferential place to undergo gluconeogenesis.
Rhonda: Yeah. So what's weird is that...I don't know the answer to your question. I know that many tissues...and this has been shown through the work of George Brooks at UC Berkeley who actually pioneered the lactate shuttle hypothesis and the theory. But it's been shown that it gets taken up by the liver, it gets taken up by the muscle, it gets taken up by the brain. In fact, exercise itself has been shown to preferentially cause the brain to the take up more...
Peter: Can we measure...I don't know if you read this literature but there was a lot of really interesting work back in the '60s done at Harvard with real fasting experiments. I mean 40-day fasts. So you'd have inpatient subjects given nothing but water and minerals for 40 days. And it was done to basically demonstrate what the steady-state fasting levels of glucose, insulin, BHB, and acetoacetate would be. And it's actually quite interesting, right? So you take a normal person. We'd take you and let's say your insulin level is 10, your glucose level is 95, your BHB level is unmeasurable because you're on a normal diet, and your acetoacetate level is unmeasurable, and then we just fast you.
And it turns out that within about seven days, you'll be at a ketone level of 5 to 7 millimolar, glucose will be down to 3 to 4 millimolar, which is, call it 60 to 70 milligrams per deciliter. And you will stay at those levels in...you know, at the end of the 40 days, they're still in those levels.
Rhonda: So they stay the same.
Peter: So glucose remember really goes away. What's changing is the consumption by the neuron which goes from, at the initial state, being about a 100% glucose...of course, I don't think they were measuring lactate then so we don't actually...
Rhonda: Were they looking at neuron or just brain? Was it astrocytes or neuron...
Peter: They were probably just looking at brain. Yeah. But it would fall to maybe 40% or 50%, the rest of it being made up by the combination of the ketones. And it's interesting that they never went to zero, right? So even to your last day of life, if you're being starved to death, you still have glucose in your blood. And so it's kind of interesting that, like...what percentage of overall brain metabolism do you think is driven by lactate? It must be very, very small and reserved for a very, very specific subset of neurons or astrocytes or...
Rhonda: Well, the astrocytes are using the glucose and they're generating lactate. So the lactate doesn't have to get in.
Peter: So we're not even seeing that, so that might be the issue. So that's probably why the liver doesn't matter because it's...
Rhonda: Yeah, during exercise, I mean. But it has been shown that lactate will cross over the blood-brain barrier during exercise as well. But that is why it doesn't have...
Peter: But the dominant source is...
Rhonda: The astrocytes, yeah. The astrocytes are making it in the brain. And what's fascinating is...
Peter: So astrocytes don't have mitochondria?
Rhonda: They do.
Peter: So why do they make all the lactate?
Rhonda: I think they make the lactate because that's how the neurons are getting their energy. I think that's just the way it works out.
Peter: So it's sort of a Warburg effect. The Warburg effect, of course, to me is interesting because I don't buy the argument that the Warburg is due to defective mitochondria.
Rhonda: It's not. Warburg showed that...I mean he...
Peter: No, there are still a lot of people who think that it's that cancer affects of mitochondria, and that's why the Warburg. But I think it's just that the cancer cell's smart enough and it's optimizing for cellular building blocks, and it sounds like the astrocyte is doing the same thing.
Star-shaped cells found in the brain and spinal cord. Astrocytes facilitate neurotransmission, provide nutrients to neurons, maintain neuronal ion balance, and support the blood-brain barrier. Astrocytes also play a role in the repair and scarring process of the brain and spinal cord following traumatic injuries.
A chemical produced in the liver via the breakdown of fatty acids. Beta-hydroxybutyrate is a type of ketone body. It can be used to produce energy inside the mitochondria and acts as a signaling molecule that alters gene expression by inhibiting a class of enzymes known as histone deacetylases.
A highly selective semi-permeable barrier in the brain made up of endothelial cells connected by tight junctions. The blood-brain barrier separates the circulating blood from the brain's extracellular fluid in the central nervous system. Whereas water, lipid-soluble molecules, and some gases can pass through the blood-brain barrier via passive diffusion, molecules such as glucose and amino acids that are crucial to neural function enter via selective transport. The barrier prevents the entry of lipophilic substances that may be neurotoxic via an active transport mechanism.
A metabolic pathway in which the liver produces glucose from non-carbohydrate substrates including glycogenic amino acids (from protein) and glycerol (from lipids).
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
A physiological condition in which cells fail to respond to the normal functions of the hormone insulin. During insulin resistance, the pancreas produces insulin, but the cells in the body become resistant to its actions and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level.
Lactate is thought to participate in a sort of "lactate shuttle" where, after being produced in muscle from exercise, it is transported in to tissues like the heart, and brain, where it is used as an energy source. Lactate is one of many molecules that falls under a loose group of molecules referred to as exerkines, a broad group of exercise-induced hormonal-like factors. Evidence suggests that lactate is the preferred fuel of the brain. Additionally, rodent studies suggest that lactate mediates some of the benefits of exercise on learning and memory via inducing neuronal brain-derived neurotrophic factor (BDNF) expression.[1] In clinical studies, lactate shows promise as a treatment for inflammatory conditions including traumatic brain injury and as a means to deliver fuel to working muscles.
Lactate that is produced from an oxygen-independent metabolic pathway (glycolysis) is shuttled to various tissues including muscle, heart, and brain, where it is used as a substrate for oxygen-dependent energy production.
The thousands of biochemical processes that run all of the various cellular processes that produce energy. Since energy generation is so fundamental to all other processes, in some cases the word metabolism may refer more broadly to the sum of all chemical reactions in the cell.
Tiny organelles inside cells that produce energy in the presence of oxygen. Mitochondria are referred to as the "powerhouses of the cell" because of their role in the production of ATP (adenosine triphosphate). Mitochondria are continuously undergoing a process of self-renewal known as mitophagy in order to repair damage that occurs during their energy-generating activities.
In the circulatory system of animals, a portal venous system occurs when a capillary bed pools into another capillary bed through veins, without first going through the heart. Both capillary beds and the blood vessels that connect them are considered part of the portal venous system. When unqualified as just “portal venous system," this often refers to the hepatic portal system. For this reason, "portal vein" most commonly refers to the hepatic portal vein.
The observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.
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