Monday, 26 March 2012

Ketosis - Implications from Veech's latest paper

Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet.

Peter@Hyperlipid should hopefully be making a much more thorough post on Veech's papers in the future but in the meantime I thought id list here some interesting points and possible implications from his latest paper linked above.


Surprisingly, Veech opens with the observation that the degree of Ketosis that is usually reached on a Ketogenic diet is, at best, "modest". He goes on to further state that almost complete avoidance of all carbohydrate calories is needed to get insulin sufficiently low enough to keep adipose tissue lipolysis high enough to fuel increased ketogenesis levels.

Recall that, the liver will in general produce ketones as fast as it can, and the only thing that stops the liver doing this is insulin and the availability of free fatty acids coming from lipolysis from the adipose tissue. Also recall, that ketones have a negative feedback loop to help control thier production rate, since adipocytes possess receptor HM74A that is suppose to bind beta hydroxybutyrate and reduce lipolysis. This same receptor also binds nicotinic acid, and is the reason that a niacin shot reduces lipolysis, at-least in the short-term.

However, insulin is required for this beta hydroxybutyrate feedback loop to work, and this is why type 1 diabetics are at a danger of ketoacidosis. When you have no or very low insulin, and lots of free fatty acids, the liver starts churning out ketones at light speed.

Further implications arise here also, there is strong anecdotal evidence amoung low-carbers that they tend to lose more weight with protein restriction aswell as Carb restriction, the so called atkins "fat fast". The avoidance of protein may well lead to even further lowering of insulin levels and thus even further increased ketogenesis. Further anecdotal evidence comes from coconut oil consumption, some people report increased weight loss and the breaking of a weight loss plateau from coconut oil, which is well reported to further increase ketone levels.

Veech has a short mention of the so-called deleterious affects of ketogenic diets, he mentions increased cholesterol, increased serum FFA, and incidence of fatty liver in mice. Hmmmm, sadly even being intelligent as im sure Veech is, doesn't always protect you from mainstream bias it seems. Pity.

Veech's team have manufactured something called a Ketone ester to help investigate the affects of high ketone levels without the complications of poor palatability on atkins fat fast diets and the so called deleterious metabolic affects mentioned above. It seems with Ketone esters, we can achieve all the benefits of high ketone levels while still eating a modest high carb diet! Good Job!


Anyway, in the next paragraph, Veech touches on how ketogenic diets are associated with reduced weight gain and even weight loss, but he says that its unclear if this is from reduced caloric intake, or increased energy expenditure. Me personally, I would say it is both, and one of the reasons for that is increased incretin secretion. Veech mentions how Ketogenic diets do not always increase activity levels, so if there is increased energy expenditure, it may not because physical movement is higher, Veech then goes on to say that increased signalling in the PPAR receptors and increased uncoupling proteins may be the answer.

Both high-fat ketogenic and high-fat non-ketogenic diets have been shown to increase UCP1 in brown adipose tissue, but Veech is not initially sure if its from increased PPAR signialling or not.


Now are are onto the experiment, where Veech's team feed mice a normal diet and a diet supplemented with ketone ester. Both diets are actually, relatively high in carbs, and without the addition of Ketone ester's, the mice in the ketone ester diet would not have had any kind of increased ketosis. Caloric content of both diets were roughly equal.

The first obersvation made was that, the ketone ester group gradually started consuming fewer calories as the concentration of ketones in the blood rise, and this is in agreement with many previous findings that in general high levels of ketones in the blood reduce appetite. This affect stabilized after 1 week, such that in further weeks, no further drop in appetite was observed.

Initially, the ketone ester diet group lost approx 12-15% of their body weight, before stabilizing at a new low nadir. The dreaded weight loss plateu! The mice were eating Ad Lib, so perhaps this can explain why people following a ketogenic diet initially experience weight loss only to eventually stall. At some point, some kind of calorie restriction could be needed to escape the nadir. Carb re-feeds also tend to work, and the reason for this is because when in deep ketosis and glycogen depleted, Carbs essentially go only towards glycogen synthesis.

Speculation here, but perhaps having a carb only day ( no protein, no fat ) after being in deep ketosis and glycogen depleted could essentially be a zero calorie day as far as your body is concerned.

Another interesting result was that, ketone levels were substantially higher at night than at daytime ( over 50% higher! ), hhmm, so if you want the benefits of high ketone levels, perhaps its better to keep your food away from bedtime. (Later on in the discussion section, Veech reports that circadian ketone levels are different in mice and rats, and that in rats, ketone levels are more or less constant, isnt it great we know so much about rodents!!!!! )

Further, the brown adipose tissue of mice on the ketone ester diet had substantially higher mitochondria content, 70% more mitochondria, and they were also 120% larger! Still further, the lipid droplets were more fragmented in the ketone group, and as we have seen here, lipid droplet fragmentation is associated with increased energy expenditure.

Looking down the results, there is a mention for our friend PGC-1 alpha, recently highlighted in the exercise study, as being the master controller for mitochondrial bio-genesis. Veech recorded 100% increased PGC-1alpha in the ketone ester group, so there is strong and direct evidence here that ketogenic diets and deep ketosis help you get new mitochondria. The workings and logic here is simple, if your demand for fat oxidation is higher, your body will make new mitochondria in response.

Another unexpected finding perhaps was that insulin sensitivity was significantly higher in the group fed the ketone ester diet, despite there still be substantial Carbohydrate in their food. But, Veech mentions how 24hr energy expenditure was essentially the same between the 2 groups and this was the reason for this similar body weights. HOWEVER, the resting energy expenditure was 14% higher on the ketone group.

Finally, its worth pointing out that Veech notes some metabolic differences in how Rats vs mice are on the ketone ester diet, and it can only make one wonder, if this difference is already so severe on 2 specie of animals that are so closely related, how much different is it going to be in animals that are even more distantly related, rodents vs humans?


  1. I forgot to mention, another implication of this paper is that, high levels ketosis actually CAUSES low insulin.

    How does it do this? By increased insulin sensitivity? Who knows.

    1. Elsewhere, Veech has pointed out that ketones act like insulin and raise glucose within the cell - this is not via GLUT4 - lower glucose in the circulation would call forth less insulin from the pancreas and cause low insulin

  2. I have heard that ketones in the brain promote metabolic health, and this may be another mechanisms VLC diets are superior for long term weight control.

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