PLMI Blog

The intricate dance between genes, environment, and hormones forms a crucial part of our understanding of health. The role of epigenetics (modifications above the genome that influence gene expression, without altering the underlying DNA sequence) is particularly notable. This interplay is pivotal for understanding the development of chronic health conditions, such as the ability of chronic stress to cause epigenetic changes that can lead to chronic health conditions, or estrogen’s role in epigenetic regulation of adipogenic genes.

Chronic Stress Induces Alterations in Cortisol Response

Chronic stress triggers a cascade of hormonal alterations, particularly within the hypothalamic-pituitary-adrenal (HPA) axis, which regulates cortisol production. Cortisol plays an integral role in the stress response by mobilizing energy stores, suppressing immune function, and preparing the body for immediate action. Prolonged elevation of cortisol levels, however, can disrupt hormonal balance and cause alterations in metabolic and immune function (1).

In fact, research demonstrates that chronic stress can even induce epigenetic changes—including DNA methylation, histone modification, and non-coding RNA regulation that impact the expression of genes involved in the stress response (1). These alterations can impede the body’s ability to appropriately modulate cortisol production, thereby increasing vulnerability to stress-induced health conditions, especially for those with genetic predispositions.

The dysregulation of cortisol levels also disrupts other hormonal pathways, primarily insulin signaling. Elevated cortisol levels interfere with insulin sensitivity, promoting insulin resistance, which is involved in the development of type 2 diabetes. Metabolic dysfunction is often further compounded by systemic inflammation and oxidative stress, which are contributing factors to the progression of obesity and other metabolic disorders (2).

Chronic stress can also result in adrenal fatigue, impeding thyroid function, increasing susceptibility to hypothyroidism, which slows down metabolism, or hyperthyroidism, the overproduction of thyroid hormone, resulting in accelerated metabolism.

Estrogen’s Role in Epigenetic Modulation of Adipogenic Genes

Estrogen governs a number of biological processes and plays a central role in epigenetic modifications that modulate fat storage and metabolism. Estrogen influences the expression of genes that regulate adipogenesis—the process in which stem cells differentiate into adipocytes—which store fat and influence metabolism. Hormonal imbalances can lead to changes in adipocyte function, influencing fat storage and the accumulation of visceral fat, associated with insulin resistance, elevated cortisol levels, and inflammatory cytokine release—all of which are contributing factors to metabolic dysfunction (3).

Genetic variants can also alter estrogen’s effects on adipogenesis (2). Estrogen receptor alpha (ESR1) gene variants have been shown to influence the body’s response to estrogen, underscoring the role genes have in obesity, as well as the importance of lifestyle in mitigating risk. Hormonal balance through stress reduction, sufficient nutrition, sleep, and movement, therefore have crucial roles in supporting metabolic health.

Epigenetics & Disrupted Cell Signaling

Patterns of genetic expression involved in insulin production and sensitivity are significant to metabolic health. Epigenetic alterations, including changes in DNA methylation or histone acetylation, regulate the expression of insulin-related genes. Chronic stress, poor sleep and diet, and environmental toxins can greatly influence these epigenetic processes, disrupting insulin signaling and insulin resistance—impeding the ability of cells to respond efficiently to insulin—often resulting in altered metabolic functions.

Genetic variants, including those in the COMT (catechol-O-methyltransferase) gene, influence the body’s stress response, neurotransmitter metabolism, and estrogen metabolism—all of which have implications for insulin regulation. Notably, variants in the COMT gene can compromise the body’s ability to respond to stress and inflammation, which can impede metabolic health. Variants in the MTHFR gene, involved in folate metabolism, have also been demonstrated to influence insulin sensitivity and metabolic health (4).

The relationship between chronic stress, hormonal imbalance, and insulin resistance underscores the importance of considering the role of genes and environmental (lifestyle) factors when addressing metabolic health.

Hormonal, Metabolic Pathways & the Epigenome

Subsequent hormones, including leptin, ghrelin, CCK, and peptide YY, also interact with the epigenome to modulate appetite, fat storage, and energy expenditure. Leptin, produced by adipocytes, signals satiety, while ghrelin, produced in the stomach, stimulates hunger (5). Dysregulation of these hormones, often driven by chronic stress or hormonal imbalances, can result in altered eating behaviors, making one more prone to weight gain. Moreover, alterations in gene expression related to these hormones can impact brain regions involved in appetite regulation, further compounding metabolic dysregulation associated with obesity and diabetes. Stress-induced epigenetic modifications can affect the expression of genes involved in these hormonal pathways, exacerbating metabolic dysfunction.

The Vagus Nerve—Modulator of Homeostasis

The vagus nerve comprises 75 % of the parasympathetic nervous system, playing a role in modulating stress and overall health (6). Through its influence on the HPA axis and autonomic nervous system, the vagus nerve helps modulate insulin secretion and glucose metabolism. Chronic stress can disrupt vagal tone, impeding the body’s ability to regulate insulin production, among various other processes, and may contribute to insulin resistance. Restoration of vagal function through techniques such as deep breathing, sleep, meditation, and other stress-reduction practices may help improve hormonal and metabolic health (4). The gut microbiome is also greatly impacted by stress, and is an essential modulator of metabolic, hormonal, nervous, and immune health. As the gut microbiome encodes for nearly five million genes, this is essential for expressing genetic expression in favorable ways (7).

Mental Health Implications of Epigenetics

The mental health implications of chronic stress are profound. Epigenetic modifications in response to early life stressors can lead to long-term alterations in HPA axis function, essential for mediating the body’s stress response. Dysregulation of the HPA axis, including impaired cortisol response, can result in alterations in stress sensitivity. Epigenetic alterations in other genes involved in neurotransmission, such as BDNF (Brain-Derived Neurotrophic Factor), have been shown to play a role in mental health conditions. These alterations can result in compromised ability to adapt to stress (8).

Research suggests that early life stress can induce long-term phenotypic adaptations, increasing susceptibility to mental health conditions. These modifications, which can alter gene expression patterns within specific cell types, are pivotal in the brain’s response to environmental stimuli.

Findings underscore the conjunction of genetic predispositions and epigenetic alterations in variations to stress response (8, 9). Psychoneuroimmunology (PNI) demonstrates the connection between chronic stress and induced hormonal, nervous, and immune alterations (10). A growing body of research also highlights the role inflammation has in impeding metabolic, hormonal, microbiome, and mental health (11-14). Inflammation can result from a combination of genetics and lifestyle factors.

Early life stress or trauma can lead to long-lasting molecular changes, such as epigenetic modifications that are central to understanding the combined effects of genetic and environmental factors in mediating and influencing health. Epigenetic modifications have the ability to alter genetic expression through mechanisms that regulate the brain’s response to stress and trauma. These processes can also contribute to the development of stress-related mental health conditions, such as depression and anxiety (1).

DNA methylation, particularly in genes such as NR3C1 which encodes the glucocorticoid receptor—significant in modulating stress, metabolic and immune function—has been identified as an integral epigenetic modification that influences an individual’s response to stress (15). Methylation of this gene leads to changes in the regulation of cortisol and the HPA axis, and has been correlated with psychosocial stress reactivity. These epigenetic alterations have also been implicated to be passed down generationally, potentially affecting an individual’s ability to adapt to and manage stress (8). Alterations in cortisol production from chronic stress can increase the risk of mental health conditions from a multi-systemic perspective.

Epigenetic changes that result from chronic stress are not fixed; they can be influenced by lifestyle factors, such as diet, exercise, and stress management techniques. These interventions may help to reverse some of the adverse effects of stress on metabolic, hormonal and mental health (1).

Genetic Variants, Hormones & Epigenetic Alterations

Genetic variants play a significant role in how individuals respond to stress. Variants in the FKBP5 gene, which regulates the HPA axis and cortisol response, have been associated with an increased risk of stress-related psychiatric disorders. These variants interact with environmental stressors, influencing epigenetic changes that occur in response to chronic stress (1). Cortisol produced in response to prolonged stress interacts with the epigenome to modulate genetic expression and can influence the methylation of specific genes involved in stress resilience, which in turn influences how one adapts to stress (6).

The interaction between epigenetics, hormones, and genetic variants is central to the etiology of chronic health conditions. As emphasized, chronic stress induces a cascade of epigenetic changes that disrupt hormonal balance and insulin signaling, leading to long-term metabolic dysfunction. Intriguingly, research demonstrates a correlation between disruptions in metabolic, hormonal, immune, and mental health (16, 17, 18). Understanding the complex relationship between genetic variants, epigenetic modifications, and hormonal influences can provide valuable insight into the pathophysiology of stress-related conditions and inform more efficacious protocols.

Holistic Modalities for Favorable Genetic Expression

Sufficient sleep, movement, and nutrition are all strategies for mitigating stress and supporting hormonal health. Research shows that circadian rhythm is significant for modulating metabolic, hormonal, and mental health through various pathways (19, 21).

Nutrition is significant for supporting the body and mind, helping us adapt to stress (11, 13). Following a diet that is bioindividual in terms of bioenergetics, or cellular health is significant. For some, this may be adapting a low carbohydrate diet, with more nutrient dense fats and proteins. Ensuring adequate amounts of micronutrients, including Vitamin D and B vitamins,  phytonutrients, and polyphenols, is also imperative; as is supporting the gut microbiome and mitigating inflammation. Functional medicine testing can provide insight on how the body utilizes energy, among various other factors, important for deciphering personalized nutrient protocols.

Somatic modalities are also important, as research suggests trauma and chronic stress may be stored in the fascia, further underscoring the interrelationship between stress and the body (21). This highlights the importance of adapting practices such as yoga, weight resistance, and cardio for supporting vagal function and stress, as well as hormonal and metabolic health (4). Finally, biofeedback, forest bathing, and connections with others are all impactful for expressing our genes in favorable ways that support hormonal and metabolic health. While we can’t control the genes we were born with, we can influence how these genes get expressed in impactful ways through epigenetics.

Join us for this free webinar, on April 1st from 5-7 PM PDT, Clinical Advances in Genetic Analysis and Its Practical Application: DNA Core, Hormones and Mind with Jeffrey Bland, PhD, Denise Furness, PhD, and Devan Szczepanski, MD, MS. This event will provide practitioners with an in-depth perspective of the growing field of personalized medicine, focusing on the clinical validity of key genes in nutrigenetic testing.

References

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