How a Ketogenic Diet May Change Your Gene Expression

Over the past few years, ketogenic diets have become one of the most popular weight loss tools out there. Numerous studies show ketogenic diets are effective for weight loss in obese and overweight individuals and if you do a quick social media search for “Ketogenic diet” or “Keto” you will find countless anecdotes that support these scientific studies (1).

The therapeutic
benefit of ketogenic diets goes beyond weight loss. These diets have been used
for nearly a century for the treatment of childhood epilepsy and are currently
being investigated for treating other neurodegenerative diseases like Alzheimer’s
and Parkinson’s.

Despite the
usefulness of ketogenic diets, we still don’t fully understand how they work!
We know that following a ketogenic diet decreases blood glucose and insulin,
and increases concentrations of ketone bodies in blood and tissues. But a
lingering question that nutrition scientists are still trying to answer is
whether it is the presence of ketones or the absence of carbohydrates that
mediates the effects of following a ketogenic diet.

There is evidence
for both, but here I want to share one exciting aspect of the research that has
emerged in recent years: the epigenetic effects
of ketogenic diets.

A
primer on epigenetics

We now understand
that our genes do not completely determine our destiny. Our environment and diet
contribute equally if not more to our health and wellbeing. The concept of
epigenetics describes how the environment can affect our gene expression
without changing the code of our DNA.

DNA is wrapped
together with proteins called histones
in a tightly coiled complex called chromatin. When there are spaces in the
coils of chromatin,
genes can usually be read and expressed. The open-space state of chromatin is
governed by whether there is a methyl group or an acetyl group attached to
histone proteins. Methyl groups are small and keep chromatin closed while
acetyl groups are bulkier and force chromatin open.

Enzymes called histone
deacetylases (HDACs) are responsible for removing acetyl groups from genes
and turning off gene expression. DNA
methyltransferase enzymes likewise add methyl groups to genes and turn off
gene expression.

There is
currently a lot of interest in developing drugs that inhibit HDACs. Although
HDAC inhibitors have been used for the treatment of psychiatric conditions for
a while, they are being looked at now for the treatment of some types of
cancers and inflammatory diseases.

Interestingly
enough, our diet can have a profound effect on histone acetylation. The
compounds butyrate (butter and cheese) and sulforaphane (broccoli and cruciferous
vegetables) are both HDAC inhibitors we can obtain through food. Also, the
ketone body, beta-hydroxybutyrate (BHB) is an HDAC inhibitor that reaches high
concentrations when we consume very-low-carbohydrate ketogenic diets.

Beta-hydroxybutyrate

BHB is one of the
major ketones produced as a result of fatty acid oxidation when carbohydrate
intake is very low. You might have already guessed that because BHB and
butyrate seem so similar, they may have some overlapping effects. It turns out
this is correct. BHB and butyrate are both HDAC inhibitors and promote the
opening up of chromatin for gene expression.

BHB is also
understood to be a direct epigenetic regulator by binding to histones. This
process is now known as the mouthful called beta-hydroxybutyrylation and mimics
the effect of acetyl groups on opening up chromatin to promote gene expression.

The reason
ketogenic diets in particular can be such powerful modulators of gene
expression is that once you enter ketosis, BHB remains persistently elevated and
is constantly interacting with chromatin to alter gene expression. This is in
contrast to ingesting compounds like sulforaphane that likely have more
transient effects.

Ketogenic
diets and BHB alter gene expression

Two separate
mouse studies found ketogenic diets altered the expression of genes involved in
glucose and lipid metabolism. 4 weeks of ketogenic diet feeding decreased the
expression of genes involved in glucose metabolism in the muscle and heart (2). 12 weeks of ketogenic diet feeding
upregulated genes involved in cellular fatty acid uptake and fatty acid
oxidation. Interestingly, these effects were amplified by exercise.

These results
actually make a lot of sense because someone running on a ketogenic diet would
have a HUGE need for fatty acid oxidation and not as much need for enzymes that
metabolize glucose.

Although these
mouse studies are interesting, it can only give us a limited understanding of
how ketogenic diets may work in humans. Mice have a much faster metabolism,
different eating patterns, and live much shorter lives than humans. Because of
this, mouse studies are useful for studying very specific molecular mechanisms
but not good proxies for how different diets might broadly affect human health.

I hope that
future human studies will start asking some of these same questions so that we
can better understand the molecular machinery behind how ketogenic diets work
in humans. Fortunately, we are already getting a glimpse of this.

A 2019 study
published in Nature showed that a ketogenic diet upregulated the
expression of PPARGC1a and FOXO1a in human and mouse T-cells.
These two genes are important regulators of lipid and glucose metabolism (3). PPARGC1a is particularly
important because it promotes fatty acid oxidation and the formation of new
mitochondria in the cell.

The authors of
the study found that a ketogenic diet increased beta-hydroxybutyrylation of
these genes and caused their chromatin structure to open and increase gene
expression. Very cool!

Summary

One limitation in
understanding the specific mechanisms of how ketogenic diets alter gene
expression is the noise in the data. What I mean by this is that during
ketosis, there are actually three separate mechanisms that might increase
histone acetylation. The concentration of the metabolite acetyl-CoA is very
high during ketosis and it can also directly acetylate histones. Ketosis also
results in high availability of NAD+ that can activate sirtuin enzymes which,
like BHB, are also HDAC inhibitors.

One thing that is
clear, is that during ketosis, the molecular machinery of the body governing
metabolism, inflammation, and other biological processes is operating under a
different “program” that seems to be useful in some disease states and perhaps
even in healthy individuals.

Despite being used therapeutically for decades, we are only beginning to understand how ketogenic diets affect human biology. The discovery that BHB is an epigenetic regulator is especially new and exciting. I hope that upcoming human experiments will be able to validate some of the previous animal studies showing epigenetic effects of BHB and ketogenic diets and apply the results to solving problems related to energy metabolism like obesity, type 2 diabetes, and nonalcoholic fatty liver disease.

Take-home
messages

• Ketogenic diets change how our genes are expressed.
• Altered gene expression may explain some of the positive metabolic effects of ketogenic diets.
• There is still a missing link between the specific epigenetic machinery altered by ketogenic diets and altered gene expression.

References

1.    R.
Ting, et. al. (2018). Ketogenic diet for
weight loss. Can Fam Physician. 64, 906 .

2.    K.
Shimizu et al.(2018). Short-term and long-term
ketogenic diet therapy and the addition of exercise have differential impacts
on metabolic gene expression in the mouse energy-consuming organs heart and
skeletal muscle. Nutr. Res. 60, 77–86.

3.    H.
Zhang et al.(2020). Ketogenesis-generated
β-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development.
Nat. Cell Biol. 22, 18–25.