Why are mice bad at ketogenesis?

Previously I collected different studies to see how the mice perform on ketogenesis. Despite having a diet that often consists of >90% fat they produce disappointingly low BHB levels. Without thinking much about it I just assumed they are bad at fat metabolism biased by thinking they are typical high carb eating animals so they are less well adapted at burning fat.

But I may have been wrong about that idea.

A recent discussion and consequent article on exercise performance and the ketogenic diet brought up the hindrance of sufficient carnitine to import long chain fatty acids (LCFA) into the mitochondria at high intensity levels (>=80% VO2max). I looked for studies and found one that tested medium chain fatty acids (MCFA) versus LCFA at low and high intensities. And indeed MCFA metabolism at high intensity is not impaired. On the other hand, carnitine becomes less available at high intensity and we see a paralleled reduction in LCFA.

Back to our favorite lab animal… But we’re not talking about exercising mice!?! Indeed we are not but when I looked back at my overview page of the different studies with keto mice, I also mentioned a study that, instead of providing the usual fat, provided hydrogenated coconut oil and the mice were able to achieve BHB levels of >5mmol/L!

Carnitine

So this got me thinking, if they are able to produce high levels of BHB with the right type of fat then the issue must be in the import of LCFA and a reduced capacity to import them into the mitochondria. Does this mean they have an issue with carnitine availability?

We get carnitine from animal food and more so from red meat. If you had a look at the overview then you also see that the mice get a very low amount of protein, typically around 5% and occasionally only up to 10%. Could this have a limiting effect on their carnitine availability? The protein content may not be enough and then we have to see what the source of protein is because that may already be a poor source carnitine by itself.

Most of the ketogenic diet (KD) chow provides casein as a protein source so there is no naturally occurring carnitine in the diet which means the animal has to obtain it from its own production.

We may have forgotten that mice are scavengers and don’t pass on the deadly remains of other animals. They need their carnitine just as much as we do. They are not 100% herbivores.

Rodents scavenged both fresh and skeletonized remains with gray squirrels only scavenging skeletal remains. Wood mice were most active in winter and scavenged both soft tissue and bone.

https://pubmed.ncbi.nlm.nih.gov/24611615/

Carnitine science

Here I want to have a look at just a few studies of the many for available evidence that carnitine plays an important role in the fat metabolism of mice.

In a first study we see a 40% reduction in carnitine for mice on KD versus a regular diet.

Serum concentrations of β-oxidation intermediates carnitine and acylcarnitine were paradoxically decreased in STKD mice, indicating a possible dissociation between hepatic gene expression and serum content of oxidative markers (Fig. 6A).

https://www.sciencedirect.com/science/article/pii/S092544391500201X
source: https://www.sciencedirect.com/science/article/pii/S092544391500201X

In the next study in humans they supplemented healthy adults with carnitine and various conditions. These were not individuals on a KD diet. They fasted overnight and then did exercise with carnitine right before exercise. The carnitine supplementation had the strongest correlation with ketogenesis.

In conclusion, LC enhanced liver fat utilization and ketogenesis in an acute manner without stimulating EE under fat-mobilizing conditions.

https://pubmed.ncbi.nlm.nih.gov/32350175/

In the figure (a) shows a very high correlation right after exercise. (b) shows the correlation 4 hours after exercise and (c) shows the combination of a and b together with the baseline sample 1 hour before exercise.

source: https://pubmed.ncbi.nlm.nih.gov/32350175/

One more study shows a much better functioning of fat metabolism in patients who are carnitine deficient after carnitine supplementation. Their side effects remind us about the KD mice. Fatty liver, higher inflammation markers etc.. When supplementing with carnitine this all improves, including insulin sensitivity.

r/ketoscience - The Importance of the Fatty Acid Transporter L-Carnitine in Non-Alcoholic Fatty Liver Disease (NAFLD) - July 2020
source: https://www.mdpi.com/2072-6643/12/8/2178

Inflammation, glucose intolerance, hepatic steatosis and other side effects

What happens when you must eat a higher volume to get to those fewer MCFA in your diet while you can’t process the LCFA? Fat builds up. It arrives in the liver but can’t get into the mitochondria that easily so it buffers up.

Once you get fat accumulating in the liver you’ll experience insulin resistance so an OGTT will show glucose intolerance.

What doesn’t get picked up remains in circulation and goes again into fat storage. We know that increased storage of fat in the adipose causes a chronic low grade inflammation so it should not be a wonder that a KD diet in mice leads to these side effects.

So these mice are eating energy that they can’t use, naturally that also leads to weight gain which we observe in ad lib feeding.

“Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice” https://pubmed.ncbi.nlm.nih.gov/24398402/

Metabolism Speed

There is of course a reason why mice need to have a low protein intake in the lab. They have a roughly 7-fold higher metabolism than humans. It results in too much gluconeogenesis from the digested amino acids and this would hinder ketogenesis.

So on one hand we need to keep the protein low to induce sufficient BHB but on the other hand we hinder their BHB production by limiting their carnitine availability.

Solution

So do mice have an impaired fat metabolism? I guess not. It looks like their diet causes them to be deficient in carnitine.

I only see a few options to correct the model and that is to increase carnitine supplementation and/or feed MCT oil. Any other type of feeding will not represent a human ketogenic diet sufficiently. Also carnitine may reduce their BHB production due go gluconeogenesis so probably the best is to put MCT oil in the diet.

Exercise

What can we learn from this and apply in our human life? If you are on a ketogenic diet and want to compete in sports, it may be worthwhile to experiment with supplementation of carnitine before the race to maximize transport of the LCFA and somehow find a way to ingest MCT during the race for maximum availability of fat into the muscle mitochondria.

— T H E – E N D —

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