Exploring BHB’s Role in Mental Health: Epigenetic Modulation as a Metabolic Psychiatry Treatment

Estimated reading time: 16 minutes

So when we talk about ketogenic diets making ketones, and those ketones are molecular signaling bodies, this is what I mean. BHB is the most well-studied ketone body in the literature at this time. That doesn’t mean that the other ketone bodies do not have molecular signaling effects or influences. It just means that the research, at the time of this article, is focused on these effects seen in BHB.

BHB used to be seen as just a metabolic byproduct but has been gaining momentum for several years in recognition of its role in the complex process of epigenetic modulation, a role that has profound implications for neuropsychiatric disorders.

Epigenetics: The Subtle Architect of Gene Expression

Before I go into some specifics of BHB, I think it is really helpful to understand the concept of epigenetics. To explain this, I would like to use the common analogy of a library and a librarian. Imagine your DNA as a huge library with a vast collection of books full of your genetic information. Epigenetics is akin to a librarian deciding which books are taken off the shelves to be read and which remain tucked away. The librarian is super powerful in this scenario, wouldn’t you agree? The librarian does not alter the books themselves – the DNA sequence remains unchanged – but the librarian influences which parts of the genetic code are expressed or “read,” and which are not. In this library, the books (DNA) are so precious that they cannot be removed. However, when a book is selected to be read, a separate process (transcription) creates photocopies (messenger RNA; mRNA) of the necessary pages. These photocopies are what leave the library, carrying the information needed for the cell to produce proteins.

The DNA sequence in genes remains the same regardless of epigenetic influences. I think the concepts of genetics and epigenetics can be confusing to people who are unfamiliar with these concepts. If you get confused by these, you are not alone. Let’s look at some examples that help our understanding.

Consuming foods rich in Vitamin B12, such as meat, dairy, and eggs, can influence epigenetic markers. While Vitamin B12 doesn’t change the DNA sequence of genes related to nerve and blood cell health, it plays a key role in maintaining healthy DNA patterns, which are crucial for the proper expression of these genes.

Exposure to pollutants and chemicals, such as heavy metals, can result in epigenetic changes. These toxins don’t alter the actual DNA sequence of genes, but they can modify DNA pattern expression. This affects how certain genes are expressed, potentially impacting health without changing the genetic code itself.

Psychological stress and traumatic experiences can lead to epigenetic modifications. These experiences don’t change the DNA sequence within genes related to the stress response and mental health. However, they can alter how these genes are expressed through various mechanisms. This altered gene expression can impact the body’s stress response and even affect cellular metabolism and mitochondrial function since stress responses are closely linked to energy use and cellular health. Thus, while the genetic code remains unchanged, the way the body responds to stress at the molecular level can be significantly altered.

Exercise affects the expression of the PPARGC1A gene, which is important for energy metabolism. While the exercise doesn’t change the actual DNA of the PPARGC1A gene, it boosts its activity. This leads to an increase in mitochondrial production in muscle cells and better energy efficiency, all through epigenetic modifications without altering the gene’s DNA sequence.

The regulation of gene expression (aka epigenetics) is achieved through various mechanisms. In this article, we are going to learn about histone modifications, DNA methylations, and microRNAs (miRNAs), also known as non-coding RNAs. By the end, you are going to understand just a little better how the effects of BHB influence these processes crucial to gene expression in a way that influences brain health.

Understanding β-Hydroxybutyrate: More Than Just a Fuel

For those new to the blog and ketogenic diets, let’s quickly get you up to speed! β-Hydroxybutyrate is a ketone body predominantly produced in the liver during states of reduced carbohydrate intake, such as fasting or adherence to a ketogenic diet. In these states, the body shifts from using glucose as its primary fuel source to burning fats, leading to the production of BHB and other ketones. You can make BHB by following a ketogenic diet, or you can intake BHB as a supplement or a combination of the two.

Will exogenous BHB supplements treat my mental illness?

But you need to know that BHB’s role extends far beyond being a mere alternative energy source. It acts as a signaling molecule influencing a range of biological processes. Among its most intriguing roles is its ability to modulate and influence gene expression through various epigenetic pathways relevant to mood and cognitive function.

The Role of β-Hydroxybutyrate (BHB) in Mental Health: Epigenetic Influence and GPCR Interaction

So, to understand the multifaceted role of β-Hydroxybutyrate (BHB) in mental health we are going to have to explore its epigenetic impact, and specifically its interaction with G protein-coupled receptors (GPCRs). GPCRs are a large family of cell surface receptors that play key roles in transmitting signals from outside the cell to the inside. They bind with specific ligands (like hormones, NTs, and metabolic byproducts like BHB) and this activates G proteins.

G proteins, short for guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells. They are located on the inner side of the cell membrane and are activated by GPCRs.

Once G proteins are activated inside the cell, they create multiple steps of signaling cascades involving important intermediary molecules such as secondary messengers (e.g., cAMP, calcium ions) and kinases (enzymes that add phosphate groups to other proteins). Some of the signaling pathways initiated by GPCRs indirectly interact with the epigenetic machinery of the cell.

For example, the cascade they initiate may lead to the activation of kinases that phosphorylate transcription factors or other proteins involved in gene regulation. In simpler terms, when G proteins are activated, they start a chain reaction, eventually activating certain enzymes (e.g., kinases). These kinases then modify key proteins (like transcription factors) that control which genes are active in the cell. This is how a signal from outside the cell (like a hormone) can lead to changes in what the cell is doing, including changes in which genes are active.

So, all of this is very interesting, but what do we know about BHB’s role in interacting with GPCRs? GPR109A and GPR41 are specific types of G protein-coupled receptors (GPCRs) in which BHB specific effects have been identified in the research literature.

BHB activates GPR109A in adipocytes, reducing lipolysis and also in immune and endothelial cells. This activation can produce anti-inflammatory effects, potentially reducing atherosclerosis risk. How might this translate into direct effects on brain health and, therefore, provide treatment effects for mental illness and neurological disorders? Well, anti-inflammatory effects, like those provided through the interaction of BHB and GPR109A activation in immune and endothelial cells, are crucial for the brain! Chronic inflammation is a known factor in various neurological disorders, so reducing inflammation can protect the brain from neuroinflammation. Improved endothelial function enhances blood flow to the brain and ensures better delivery of oxygen and nutrients—vital mechanisms for a functioning brain and, therefore, stabilization of mood and cognitive function.

However, the effects of BHB are inhibitory or “antagonistic” in the expression of GPR41. How could BHB getting in the way of expression be beneficial? That seems counterintuitive, doesn’t it? So, let’s begin our exploration of this in the context of diabetes.

In diabetes, the unfettered expression of GPR41 is associated with a decrease in insulin secretion. This decrease is thought to contribute to the challenge of pancreatic beta cells in responding adequately to elevated glucose levels, a key feature of type 2 diabetes. GPR41 activation in pancreatic beta cells may actually play a role in inhibiting proper glucose-stimulated insulin secretion under diabetic conditions.

However, as already stated, BHB has been seen to antagonize the expression of GPR41. Why does that matter? Because antagonizing (going against or slowing down) the expression of GPR41 can have beneficial metabolic effects.

By working against GPR41, BHB potentially increases insulin secretion, thereby improving blood glucose control. This mechanism suggests a valuable role for BHB in managing diabetes, particularly in enhancing glucose tolerance and insulin sensitivity. But what about mental illness and neurological issues marked by metabolic dysfunction in the brain? I would argue that these effects are significant for brain health.

Stable blood glucose is crucial for brain function, and improved glucose regulation supports cognitive health, reduces the risk of neurodegenerative diseases, helps stabilize mood, and offers overall neuroprotection. It has been shown that BHB’s antagonism of GPR41 influences energy consumption and sympathetic nerve activity. An interaction that also affects glucose homeostasis by regulating insulin secretion.

The antagonism of GPR41 by BHB also influences sympathetic nerve activity. Regulating sympathetic nerve activity is important because it’s part of the body’s response to stress. By modulating this response, BHB can exert influence in managing stress-related effects on the brain, which we know can disrupt brain metabolism. The role of this interaction in glucose homeostasis and insulin secretion is crucial for brain health, and imbalances can lead to mood and cognitive issues and increased risk of neurodegenerative diseases.

BHB plays a significant role in inflammatory, neurologic, and metabolic illnesses as an endogenous GPCRs ligand.

He, Y., Cheng, X., Zhou, T., Li, D., Peng, J., Xu, Y., & Huang, W. (2023). β-Hydroxybutyrate as an epigenetic modifier: Underlying mechanisms and implications. Heliyon. https://doi.org/10.1016/j.heliyon.2023.e21098

It is not difficult to see how BHBs effects on GPCRs have significant implications for metabolic health, and, therefore direct effects on brain health.
And those are just the indirect effects of BHB on epigenetic expression through GPCRs. Let’s get you up to speed with the direct mechanisms involved so you can understand better why this is such a powerful therapy.

Methylation 101: Setting the Stage for BHB’s Role in Gene Regulation

BHB has powerful effects on methylation. Before we can talk about them, we should spend a moment talking about what methylation is because it is a fundamental biological process that plays an important role in gene regulation and epigenetics.

Don’t overcomplicate this word. It seems intimidating at first, but at its core, methylation is just the addition of small chemical groups called methyl groups to specific parts of our DNA or to the proteins (histones) around which DNA is wrapped. They act like ‘tags’ that can either activate or silence genes. When methyl groups are added to certain regions, they can ‘turn off’ a gene, preventing it from being used to create proteins. When these little methyl groups are not present, they ‘turn on’ a gene by allowing it to be actively transcribed into proteins. Methyl tags turn genes off, and those genes don’t make proteins. Genes that do not have a methyl tag turn on and make proteins.

In the library and librarian analogy, DNA methylation could be likened to the librarian placing specific markers or tags on certain books. These markers don’t change the content of the books (the DNA sequence) but indicate whether a book should be readily accessible or not. In this analogy, when a book is tagged by the librarian (methylation), it’s a signal that this book should not be opened or read at the moment. This is akin to how methylation in the DNA can suppress the expression of certain genes. It’s as if the librarian is saying, “This book is not needed right now; let’s keep it on the shelf and out of circulation.” Conversely, the absence of such a tag means the book is available to be read, similar to how the lack of methylation can allow a gene to be expressed.

Elevated levels of β-Hydroxybutyrate (BHB) can inhibit the activity of enzymes like DNA methyltransferases (DNMTs). DNMTs are responsible for adding methyl groups to DNA, a key process in gene regulation known as methylation. By inhibiting these enzymes, BHB can reduce the methylation of DNA, which can lead to changes in the expression of certain genes.

Let’s provide an example to facilitate your learning!

BHB inhibits enzymes that promote methylation. This inhibition by BHB allows the gene PGC-1a (PPARG coactivator 1a) to upregulate. This is really, really good. PGC-1a is crucial for mitochondrial function and biogenesis. The upregulation of this gene plays a vital role in maintaining mitochondrial respiratory function and fatty acid oxidation rates.

If you want to know what genes are influenced by BHBs effects on methylation, then you are really going to enjoy this article I wrote about just that!

The Ketogenic Diet: A Powerful Molecular Signaling Therapy for the Brain

It is widely known that ketone bodies not only serve as ancillary fuel substituting for glucose but also induce anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone deacetylase (HDAC), or G protein-coupled receptors (GPCRs) 

He, Y., Cheng, X., Zhou, T., Li, D., Peng, J., Xu, Y., & Huang, W. (2023). β-Hydroxybutyrate as an epigenetic modifier: Underlying mechanisms and implications. Heliyon. https://doi.org/10.1016/j.heliyon.2023.e21098

This cooperation between DNA methylation and histone changes is key in turning off certain genes. Such orchestrated interactions exemplify the complexity of epigenetic regulation, where multiple processes work together to finely tune the expression of genes, ultimately influencing cellular function.

Exploring the Link Between BHB and HDAC Inhibition

Next, we are going to talk about something called Histone Deacetylases (HDACs). The HDAC family consists of several enzymes, each designated by a different number, such as HDAC1, HDAC2, HDAC3, and so on, including HDAC5. These are enzymes that typically remove acetyl groups from histones, resulting in tightly packed DNA and reduced gene activity.

BHB has been shown to inhibit HDAC5, and this has been associated with neuroprotective outcomes, as it helps in blocking pathways leading to cell death. This has raised questions about the role of ketones, like BHB, in treating disorders involving genetic variations of HDAC5, such as bipolar disorder. Could the modulation of HDAC5 by ketones be a key mechanism through which a ketogenic diet exerts its therapeutic effects in bipolar disorder?

Can a ketogenic diet mediate the genetic influence of bipolar disorder?

Let’s go back to our library and librarian analogy. Imagine the librarian (epigenetics) is using HDACs (an enzyme) to pack the books (genes) more tightly onto the shelves (histones). This tight packing on the shelves makes it difficult to pull out individual books (we have all had a bookshelf like this, right?). The difficulty experienced in getting the book off the shelf reduces the likelihood it will be read (gene expression). Fewer HDACs mean more space on the book shelves and easier retrieval of books (genes). Got it? Good! Let’s keep going!

And for those without a biology background, you might wonder if methylation is somehow related to Histone Deacetylases (HDACs). They are not. They are distinctly different mechanisms. However, they are often discussed together in the same articles because these mechanisms have a collaborative nature. Areas of DNA that undergo heavy methylation can attract proteins that recognize these methylated regions. These proteins can then recruit HDACs to the site, which you are about to learn can have powerful effects.

It just so happens that BHB plays a powerful role in the modulation of gene expression by inhibiting Histone Deacetylases (HDACs). BHB’s inhibition of HDACs prevents this deacetylation, leading to a more relaxed state of DNA.

I know the word “relaxed” is odd in this context. But I am not making it up. The term “relaxed” in the context of DNA and histone modifications is appropriate and commonly used in molecular biology. When DNA is “relaxed,” it refers to a state where the DNA is less tightly coiled around histones. This relaxation is crucial for gene expression, as it allows transcription factors and other regulatory proteins easier access to specific DNA regions.

This relaxation allows certain genes, like FOXO3a, for example, to become more active. FOXO3a is involved in various cellular processes, including stress response and apoptosis (programmed cell death). The inhibition of HDACs by BHB can enhance the transcription of FOXO3a, contributing to cellular stress resistance and survival mechanisms. This effect is particularly relevant in the context of neuroprotection, which is a much-needed treatment effect in those suffering from mental illness.

I don’t want you to think that BHBs effects on HDACs is only relevant for one gene. Another relevant and important example of how inhibition of HDACs by the presence of BHB as an epigenetic modification is apparent when we look at Brain-Derived Neurotrophic Factor (BDNF)

Our results demonstrated that the ketone body BHBA could promote BDNF expression at a concentration within a physiological region (0.02–2 mM) under normal energy supply.

Hu, E., Du, H., Zhu, X., Wang, L., Shang, S., Wu, X., … & Lu, X. (2018). Beta-hydroxybutyrate promotes the expression of BDNF in hippocampal neurons under adequate glucose supply. Neuroscience, 386, 315-325. https://doi.org/10.1016/j.neuroscience.2018.06.036

BHB’s inhibition of HDACs has also been seen to lead to an increase in the expression of BDNF. BDNF is a critical gene for neuronal growth, survival, and synaptic plasticity. By inhibiting HDACs, BHB promotes a more acetylated state of histones near the BDNF gene, facilitating its transcription. This upregulation of BDNF can have significant implications for neuroplasticity, cognitive function, and potentially the treatment of depression and other mood disorders.

Understanding the Influence of BHB on microRNA Regulation

Another method of epigenetic regulation is something called microRNAs (miRNAs), which are small non-coding RNA molecules that regulate gene expression. They act as guides that can attach to specific messenger RNA (mRNA) in the cell, and when they do this, microRNAs (miRNAs) can either stop the messenger RNA (mRNA) from making proteins or slow down protein production. How do we explain the role of microRNA on epigenetic expression using our library analogy?

In our genetic library analogy, where genes are books, and the librarian represents epigenetics, microRNAs (miRNAs) are like little notes that arrive after the librarian has already chosen to read a book (gene) and photocopies (mRNA) have been made. These notes provide guidance on how often the librarian (epigenetics) should continue to access certain books (genes) or whether access should be restricted, ensuring better control over gene expression to meet the cell’s needs.

BHB extends its influence to microRNAs (miRNAs). How does BHB do this?They function by binding to specific messenger RNA (mRNA) molecules, typically resulting in the repression or degradation of those messenger RNAs. As described in our library analogy, microRNAs (miRNAs) play a role in post-transcriptional regulation by primarily fine-tuning gene expression. They may target specific messenger RNAs (mRNAs) for degradation or inhibit their translation to increase or reduce the production of certain proteins in response to a cell’s requirements.

Such processes are key components of post-transcriptional regulation that influence a wide array of cellular processes, which happen to include metabolism.

Studies done in human volunteers have shown that microRNA expression profiles were significantly altered after a 6-week regimen on a Ketogenic Diet (KD), indicating that the metabolic changes induced by a KD, which includes elevated BHB levels, can lead to changes in miRNA expression.

Overall, the volunteers on a KD displayed regulation of miRNAs targeting specific genes linked to nutrient metabolism as well as mTOR, PPARs, insulin, and cytokine signaling pathways

Nasser, S., Vialichka, V., Biesiekierska, M., Balcerczyk, A., & Pirola, L. (2020). Effects of ketogenic diet and ketone bodies on the cardiovascular system: Concentration matters. World journal of diabetes, 11(12), 584–595. https://doi.org/10.4239/wjd.v11.i12.584

But the interesting part was that the miRNAs regulated by the Ketogenic Diet (KD) targeted specific genes linked to nutrient metabolism, as well as important signaling pathways such as mTOR (mechanistic target of rapamycin), PPARs (peroxisome proliferator-activated receptors), insulin signaling, and cytokine signaling pathways. These are important pathways for brain health by modulating energy metabolism and repairing and reducing neuroinflammation.

It’s just another way that BHB can contribute to fine-tuning gene expression, impacting cellular function, and providing potential treatment effects on disease processes or metabolic states.

Conclusion

In this article, you’ve explored several mechanisms through which the presence of BHB acts as an epigenetic modulator of gene expression. Returning to our analogy of the library full of books (genes) and the librarian (epigentics), it becomes evident that BHB assumes the role of the librarian in our genetic “library.”

Much like the librarian’s influence over the library’s contents, BHB does not alter the fundamental DNA sequence itself; it leaves the DNA sequence unchanged. However, BHB plays a crucial role in influencing the epigenetic marks and molecular processes that determine gene expression. Through its impact on processes like histone modification, DNA methylation, and microRNA regulation, BHB emerges as a powerful regulator in the intricate world of epigenetics. It profoundly influences our metabolic state and can impact gene expression, influencing the functioning of multiple relevant systems that impact brain health. And so I ask, why wouldn’t it provide treatment effects for mental illness and neurological disorders?

I sincerely hope that this article has been helpful in your understanding of ketogenic diets. You have the right to know all the ways you can feel better, and with the powerful molecular signaling effects of ketones being identified in the research literature, you may be discovering that a ketogenic diet might be one of them.

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Mikami, D., Kobayashi, M., Uwada, J., Yazawa, T., Kamiyama, K., Nishimori, K., … & Iwano, M. (2019). β-Hydroxybutyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5 in human renal cortical epithelial cells. Life sciences, 222, 125-132. https://doi.org/10.1016/j.lfs.2019.03.008

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