In 1895, a biochemist by the name of Rosenfeld coined the expression "fat burns in the flame of carbohydrate." This was based on observations that cells could break down fatty acids into ketone bodies but without sufficient glucose the cells could not break them down fully into carbon dioxide and hydrogen.
The aphorism offered a simple explanation for why ketones are elevated to extreme levels in diabetes: diabetics do not use glucose efficiently, so glucose levels in the blood rise; since their cells are starved of glucose, the fat stores of these diabetics release their fatty acids and their livers break the fatty acids down into ketones, but these ketones cannot be used in the absence of glucose, so ketone levels in the blood rise and then the ketones are finally lost in the urine. Thus the diabetic is effectively in a constant state of starvation.
We now know that fat burns in the flame of oxaloacetate, which can be derived from either glucose or amino acids.
When we break down fats or carbohydrates for energy, we turn them into acetic acid, or acetate, which is a two-carbon unit. A little shuttle called coenzyme A, which is made of pantothenic acid, carries the acetate around and together we call the complex acetyl CoA. Pantothenate is also called vitamin B5 and is found abundantly in many foods but liver and egg yolks are among the highest (along with certain mushrooms, seeds, and yeast).
In order to fully harvest energy from acetate, we need to send it through the citric acid cycle, also called the Krebs cycle or the tricarboxylic acid (TCA cycle). This cycle will break the acetate down into carbon dioxide and hydrogen. In doing so, it will also release high-energy electrons whose energy can then be harvested to synthesize ATP, a major usable energy currency of the cell. Entry into this cycle is dependent on a compound called oxaloacetate.
In the presence of glucose, we convert glucose to oxaloacetate. Thus, as oxaloacetate leaves the Krebs cycle cuz it's got things to do and people to see, we can just use glucose to replenish it. In the absence of glucose, we do the opposite: we turn oxaloacetate into glucose. Thus, oxaloacetate gets depleted in the absence of glucose unless we have some other source of it. We can make oxaloacetate from a variety of amino acids, but not from fats. Thus, in the absence of dietary protein or carbohydrate, the only place to get oxaloacetate is to dig into the lean proteins found in our muscles and internal organs.
One thing I really like about The Perfect Health Diet is that although the authors advocate a low-carb diet, they devote a lot of attention to the body's need for glucose, rather than coming up with some silly aphorism like "there are essential amino acids and essential fatty acids, but there is no essential carbohydrate." The body may be able to survive without dietary glucose, but only because it can make glucose from protein. Give it only fat, and it will make that glucose — and oxaloacetate — from lean muscle tissue.
Better get a steak or potato to go with that butter!
- Emily Deans, M.D. said...
- Chris - I doubt you need to be burning predominantly ketones for the brain to see some benefit from ketosis. Zooko sent me links to so,e interesting studies on twitter - I think I will do a post on it, actually. They are familiar papers but the graphs are very interesting.
- Chris Masterjohn said...
- Emily, I don't doubt it, but the brain selectively gets the glucose when it is initially limiting, with muscles getting the ketones. Under more extensively glucose deprivation this shifts towards muscles using fatty acids and brains using ketones, which spares lean mass by reducing the need for gluconeogenesis. This is my understanding, at least, though I do need to look deeper at the primary literature on this and the differences between ketogenic diets and prolonged fasting. But my point in response to Dana was that even on a very low-carb diet with a moderate amount of protein, the brain, while perhaps using ketones to some degree, is probably still using primarily glucose. I'm very open to changing this view as I consider it tentative. I look forward to reading your post. Chris
- Emily Deans, M.D. said...
- I should say that a strict anti-seizure benefit would have to be from strict ketosis to up regulate the GABA reliably and consistently. But other conditions seem to benefit from dips into ketosis, or ketosis that just turns a ketostix. Well, post coming one of these days...
- Chris Masterjohn said...
- Hey Dr. Deans, In my experience, I can get ketostix purple just by exercising intensely and feasting on carbs. I'd be willing to bet that my brain was running almost entirely on glucose when my ketostix were as purple as they could get (granted I was eating plenty of fat including coconut fat during this time). I'm definitely not claiming dips into ketosis won't be of benefit -- I'm just saying (in my response to Dana, which I'm assuming that's what you're responding to) that in calculating the physiological glucose requirement of the brain you can't assume that a low-carb diet is going to substantially reduce it. Most low-carb diets probably keep the brain running mostly on glucose is my guess, and that's all I was saying. Chris
- Paul Jaminet said...
- Hi Chris, Great post, and thanks for the shout-out! Here are a few thoughts I had while reading: The “fat burns in the flame of oxaloacetate” discussion is an elegant summary of why 95% fat diets are unhealthy. Re Dana’s point, the body consumes a lot of glucose whether it is consumed or no. If you want to exclude carbs from the diet, you’d better eat sufficient protein! Even if you do, it’s far from clear that manufacture from protein is the optimal way to meet glucose needs. I don’t believe it is. Re ketogenic diets, I’ve migrated to the view that the optimal ketogenic diet even for clinical use should have minimal excess ketones, few excreted ketones, and a fair amount of dietary carbs and protein. Once ketones are being excreted, few tissues are taking up marginal ketones. I think the clinical ketogenic diets often overshoot the optimal amount of ketones, and undershoot the optimal amount of carbs and protein. Re Ned’s point, I’ve eaten a moderately ketogenic low-protein diet for a long time and my albumin levels have never budged. Of course I’ve never eaten a 95% fat diet … but I would imagine you would lose a lot of lean muscle mass before serum albumin levels would start to decrease. Anyway, great thought-provoking post! Best, Paul
- Another great post Chris. The way I see it is that fat can burn in the flame of anything that keeps the TCA cycle going. Even though oxaloacetate is drawn off, you can replenish it via every intermediate in the TCA cycle, because it will eventually be turned into oxaloacetate anyway. Glucose and amino acids are just two of the TCA cycle replenishing options. Another option would be odd-chain fatty acids. They can burn (somewhat) in their own flame, because the last cycle of their β-oxidation will provide propionyl-CoA, which can be turned into succinyl-CoA, a TCA cycle intermediate (not shown in the TCA cycle diagram BTW). And what about the substance that gave the cycle its name: citric acid. Perhaps that's the reasoning behind the lemon diet: burn fat in the flame of citric acid. The citric acid (and some sugar) from the lemons should be able to keep the TCA cycle going, so that would spare protein. But when you know all this, why go for the sour taste of a lemon diet? Using a sugar drink should do the trick just as well. Hmmmm, burning fat with a sugar drink? That sounds a lot like the Shangri-La diet by Seth Roberts. John
