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.
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!
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.
- 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.
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 ?-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development. Nat. Cell Biol. 22, 18–25.