Ketosis Part II: Regulation

Now that we have a good idea of what ketone bodies are, and how they start to get formed and where I think it is time to loot at the regulation of the process.  I think what has been really interesting to me in researching this topic is that I expected to find some sort of “master switch” for ketosis.  What I mean by that is I figured that something would happen that would turn on ketosis, and as such you are either in ketosis or out of ketosis.  However, as we saw in the last article everyone produces small amounts of ketones at rest, and ketosis is physiologic process that just happens when the substrates are available and are not being used for other processes. 

There are two main types of regulators for ketogenesis, and while they may seem very different to some people, I think they are rather similar.  It all depends on what energy our body is using, and in what amounts.  Ketogenesis can be controlled either through physiologic processes or through enzymatic processes.  We will start with the physiologic ways that ketosis is controlled, and then go to the enzymatic/hormonal ways, since those are probably a bit more complicated.

When we talk about physiologic processes that induce ketosis we are talking about what is going on in our body to make it start naturally producing ketone bodies.  There are three main ways this happens, and a fourth little trick people use to jump start the process (any guesses now what that is?).  The three ways are: starvation/fasting, prolonged exercise, and a low carb/high fat diet.  Let’s take a look at each of these in turn.

Fasting/Starvation

The activation of ketogenesis to fasting/starvation is well documented (1, 2, 3). Fasting induced ketogenesis happens through a pretty basic mechanism: glucose/glycogen are depleted or saved for use by the brain, fatty acids are mobilized by the adipose tissue and broken down into acetyl-CoA through ß-oxidation .  This is pretty basic biochemistry.  As we learned in the previous article once we build up enough Acetyl-CoA and have no glucose around to offer up some oxaloacetate, we turn to ketogenesis. In fact, when fasting is initiated we see an almost identical association of acetyl-CoA levels in the liver and production of acetoacetate (4).  It is important to note here that this type of ketogenesis is performed almost entirely by liver cells, or hepatocytes.

I think that this again shows what a simple process ketogenesis can be.  There is a build up of acetyl-CoA in liver mitochondria so to get rid of it we turn it into ketone bodies.  However, how does this process stop then?  Well, the refeeding with a high carb meal can curtail ketogenesis within 1 hour! Not only that, but an intravenous injection of insulin can stop ketogenesis within 10 minutes (4)!

Exercise

Exercise is another potent way to induce ketogenesis. Since 1909 researchers have documented the ability of exercise to stimulate ketosis in the right individuals (5).  This happens through a similar mechanism as fasting induced ketosis.  When we exercise we use up our bodies glucose/glycogen stores for quick energy to fuel the exercise.  Once we burn through these our bodies will start to break down fatty acids and ketogenesis will begin.  However, this process only appears to happen in certain individuals. 

First, glycogen content has a huge effect on exercise's ability to produce ketones.  From the abstract of one study we can see that when both muscle and liver glycogen stores are high there is almost no ketone production (6).  Since glycogen content is highly related to the amount of carbohydrate you are consuming, this can be seen as merely an adaptation to a low carb diet in most cases.

Also, age and degree of training may play a role in post-exercise ketone production.  In one fairly comprehensive study about the effects of exercise on ketone prodction the authors found that some older patients and untrained patients had higher levels of ketone bodies after exercise, but the effects where highly variable (7).  From this study it looks like the effect of exercise to induce ketogenesis is primarily due to the bodies metabolic flexibility and efficiency.

Diet

And now we get to the big one, the diet's ability to produce ketogenesis!  Most of us already know that a high-fat, low-carb diet will increase the amount of ketone bodies we produce.  In this figure from one of the earliest studies on ketogenesis we can see that the high-fat diet produces significantly more ketone bodies than either the control or high-carb diet (8).

Now not only does a high-fat diet induce ketogenesis through providing more acetyl-CoA substrates like we talked about previously, it can also cause the increase in the key enzymes needed to produce ketone bodies.  This cool graph shows the liver HMG-CoA synthase levels in newborn rats fed either a high-fat diet or a high-carb diet (9).

As we can see from this the high-fat diet induces a nearly 50% increase in the key enzymatic regulator of liver mitochondrial ketone production.  I think this just gives more credence to just how much our food can affect our genes!

Well, we have seen just how much a high-fat diet can affect both our ketone body levels, and our ketogenic genes, but now I’d like to talk about a topic that doesn’t seem to get much play when talking about ketogenesis: protein levels.  In one really interesting study researchers fed rats a high-fat, low-carb diet, but varied the amounts of protein they gave the rats (10).  They had three intervention groups: a Low-carb 75%fat 10% protein diet (LC75/10), a low-carb 65% fat 20% protein (LC65/20), and finally a low-carb 55% fat 30% protein (LC55/30) diet.  The results were very surprising to me.  Lets first look at the BHB levels in the blood the researchers found.

Wow!  While it looks like the LC55/30 group has elevated BHB levels, the authors concluded that only the LC75/10 and LC65/20 were statistically significant, and the LC65/20 only moderately so.  But, jut by increasing protein to 20% of calories you nearly half the ketogenic potential of the diet.  

Another interesting thing these researchers looked at was how much gluconeogenesis (formation of new glucose from other subtrates) was happening. This next figure was the expression rates for one of the key enzymes in gluconeogenesis.

Again, wow!  When on the highest protein diet we have almost no gluconeogenesis happening.  No glucose synthesis, no ketone synthesis, what are we going to be using to fuel our big brains?  I think this is huge in why people fail on low-carb diets.  If you eat a high enough protein diet in addition to taking out most of your carbs you won’t have energy to use, especially energy for your brain.  It is completely unsustainable.  Now, I don’t think you need to go and cut out most of the protein in your diet just yet, in a later post in this series I will provide some practical recommendations based on the research I present, and I think most people should be fine with a protein intake higher than 10% of calories.

To summarize:

What a lot of information we have covered in this post, I think we need to summarize our finding again.

• There are three main physiologic ways that ketogenesis is regulated: Fasting, exercise, and diet.
• During fasting the breakdown of stored fats by the liver increases the acetyl-CoA levels in the liver and leads to ketone body production
• Exercise can produce ketogenesis, however the effect is smalller and usually only seen in peole who are adapted to low-carb eating or have low glycogen levels.
• High-fat diets can help to increase ketogenesis two ways: they increase the acetyl-CoA levels and thus ketone body levels, and they also increase the expression of key ketogenic enzymes.
• Protein levels have a huge effect on the ketogenic potential of a diet, and just eating a high-fat diet is not enough to sustain ketosis
• A high-protein, low-carb diet is highly unsustainable due to low ketone body production and low gluconeogenesis, providing very little energy for our brain.

Next we will cover the other half of ketogenesis regulation: hormonal/enzymatic which we did talk a bit about here.  I know these articles are longer, and more complex than the other ones I have written so if you have questions please leave them in the comment!  Stay tuned for Ketosis Part III: Hormonal/Enzymatic regulation.