In a society saturated with diet culture, food rules, and weight loss programs, the concept of eating without counting calories or adhering to strict rules can seem foreign. Diet culture often presents eating as a structured activity, with an "eat this, not that" mentality. However, eating is a deeply personal and individual experience that varies from person to person. Our relationship with food begins in childhood and evolves over time, influencing our eating behaviors as adults. The fast-paced nature of modern life also impacts our mealtimes, often leaving us with limited time to eat mindfully.
Mindful eating offers a refreshing alternative to restrictive diets. It is an approach that encourages individuals to fully immerse themselves in the eating experience, focusing on the sensual aspects of the food being consumed. With increased awareness during meals, we can better identify our eating behaviors, such as eating quickly or overeating. The primary goal of mindful eating is to move away from dieting, which typically involves short-lived and restrictive eating patterns focused on achieving a specific outcome, such as weight loss.
Understanding Mindful Eating
Mindfulness, in general, refers to the act of being conscious and aware of what we choose to focus on in a given moment. Mindful eating applies this concept to the act of eating, encouraging individuals to pay attention to the present moment and fully engage with the experience of eating. Unlike diets, mindful eating is not about following strict rules or measuring portions. Instead, it emphasizes creating an individualized experience driven by physiological cues and senses.
Incorporating Mindful Eating into Daily Life
Mindful eating begins well before we physically put food in our mouths. It starts with noticing the first signs of hunger or a desire to eat. Often, we eat for reasons other than physical hunger, such as emotional hunger, stress, boredom, or even difficult situations. As a dietitian, Lauren encourages patients to pause and reflect on their reasons for eating to distinguish between physical and emotional hunger.
Once the "why" behind eating has been determined, the next step is to set up an ideal environment that fosters mindfulness. In our fast-paced society, we often find ourselves distracted during mealtimes. To create the best setting for mindful eating, it is essential to eliminate distractions such as watching TV, being on the phone, driving, or any external stimulus that shifts focus away from the eating experience. The goal is to create a calm, non-distracting environment to best practice mindfulness.
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With the "why" and "where" established, we can now shift our focus to the food itself and begin eating. Mindful eating is about immersing ourselves in the present moment, using our senses of smell, taste, sight, and feeling to fuel this unique eating experience. It is helpful to chew food thoroughly and pause between bites, taking time to savor each mouthful.
While eating, it is important to check in with ourselves and assess our fullness. Are we satisfied with the amount we have consumed, or could we eat more? A useful tool for gauging hunger and fullness is the Hunger and Fullness Scale. By assigning a number to our hunger/fullness level that correlates with a specific description, we can better assess our needs at any point during the eating process. Noticing satisfaction can help avoid overeating and feeling uncomfortable or stuffed. It is a good idea to experiment with different levels of fullness, as physical cues can vary from person to person. Every time we eat is an opportunity to practice mindful eating, so there is no need to worry if we overeat sometimes. We can always try again the next time we eat.
The Benefits of Mindful Eating
Practicing mindful eating can offer a new perspective on the eating experience and help foster a healthy relationship with food and our bodies. This approach can be empowering because we are in control of our decisions around food and can create our own unique eating approach that works for us.
The Role of Metabolic Alterations in Disease Progression
Systemic metabolic alterations can significantly impact the course of various diseases, including prostate cancer. Epidemiological studies have shown that saturated fat intake and obesity are associated with increased prostate cancer progression and mortality. Given the rising rates of obesity and diet-associated metabolic diseases, combined with the high frequency of newly diagnosed prostate cancers in developed countries, a deeper understanding of the mechanistic links between metabolism and disease is crucial.
Preclinical and clinical studies have demonstrated that systemic metabolic alterations resulting from fat-enriched diets and obesity can cooperate with tumor-initiating genetic alterations to promote disease progression. Modulation of insulin/insulin-like growth factor 1 levels, phosphatidylinositol-3-kinase/mammalian target of rapamycin complex 1 pathway activation, and pro-inflammatory stimuli have been implicated in this process. Furthermore, metabolic rewiring is closely connected to epigenetic changes, as metabolites act as substrates or cofactors for epigenetic remodeling.
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The Impact of High-Fat Diet on Prostate Cancer
In prostate cancer, the landscape of epigenetic alterations varies considerably as the disease progresses. However, the influence of metabolic alterations triggered by increased fat intake and/or obesity on prostate cancer epigenome rewiring and disease progression remains largely unexplored.
The oncogene c-MYC (MYC) is a key driver of human prostate cancer tumorigenesis and progression. MYC protein is often overexpressed in early stages of the disease, and amplification of the MYC oncogene is associated with poor disease-specific survival. In murine models, MYC overexpression faithfully recapitulates the primary human disease.
A hallmark of MYC overexpression in tumors is the induction of a global metabolic reprogramming to support cancer cell survival and growth. Previous studies have shown that increased dietary fat intake significantly alters the biological behaviors of prostate cancers driven by MYC, suggesting that this preclinical model is ideal for investigating the interplay between high-fat diets (HFD), oncogene-driven metabolic vulnerabilities, and epigenetic alterations in prostate cancer progression.
Research has integrated metabolome, epigenome, and transcriptome profiling to identify HFD-driven alterations that foster prostate cancer progression in vivo. The findings demonstrate that increased fat intake amplifies MYC hallmarks and further enhances MYC's transcriptional program. Importantly, a fat-induced MYC signature with clinical utility has been identified, which can help identify patients at higher risk of a more aggressive, lethal disease. These findings suggest that a substantial subset of prostate cancer patients, including some without MYC amplification, may benefit from epigenetic therapies targeting MYC transcriptional activity or from dietary interventions targeting the metabolic dependencies regulated by MYC.
High-Fat Diet Reprograms Cancer Metabolome and Accelerates Progression
To examine the potential role of HFD in promoting metabolic rewiring of prostatic tissues, studies have compared mice that overexpress a human c-MYC transgene (MYC) in the prostate epithelium to wild-type littermates (WT) that were fed either a HFD (60% kcal from fat; lard-rich in saturated fat) or a control diet (CTD; 10% kcal from fat). Irrespective of their genotype, mice that were fed with HFD developed the hallmarks of a diet-induced obesity phenotype, including increased body weight, liver steatosis, hyperinsulinemia, hyperglycaemia, and a decrease in circulating 1,5-anhydroglucitol (a marker of short-term hyperglycaemia).
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MYC overexpression, irrespective of HFD, resulted in extensive cellular epithelium transformation to prostatic intraepithelial neoplasia (PIN) in the dorsolateral (DLP) and ventral (VP) prostate lobes. Conversely, the anterior prostate (AP) remained mostly unaffected. No presence of PIN was detected in the prostate lobes of WT animals fed a HFD. Increased tumor weight and cell proliferation were evident in the HFD-fed mice compared to the CTD group, confirming previous reports that HFD significantly enhances the progression of MYC-driven prostate cancer.
The lack of a HFD-dependent phenotype at 12 weeks of age, combined with the robust and uniform transition to PIN triggered by MYC overexpression observed in the VP, enabled researchers to investigate metabolic alterations driven by HFD before the appearance of a more aggressive, HFD-dependent phenotype. Untargeted metabolomics identified 414 metabolites in the prostate. As previously described, MYC induces a profound metabolic reprogramming in the VP, affecting more than half of the metabolites detected, including metabolites related to glutamine, glucose, lipid, nucleotide metabolism, and protein synthesis. Importantly, these MYC-driven metabolic vulnerabilities were enhanced by HFD. Indeed, HFD resulted in increased levels of metabolites from glycolysis (i.e., lactate), glutaminolysis (i.e., glutamate), glutamine-metabolism-related pathways including substrates, intermediates and final products of the citric acid cycle, nucleotide synthesis, amino acid metabolism (e.g., arginine, proline, aspartate and histidine), urea cycle, lipid metabolism, and hexosamine biosynthesis. These features were also supported by Metabolite Set Enrichment Analysis (MSEA). Conversely, HFD had little impact on the WT prostatic metabolome, affecting only a total of 12 metabolites, nine of which were glycerophospholipids, and lowering 1,5-anhydroglucitol levels, in line with HFD-driven increase in circulating glucose and reduction of serum 1,5-anhydroglucitol.
Notably, MYC overexpression led to a significant decrease in s-adenosylmethionine (SAM), a member of the methionine cycle and the ultimate methyl donor required for methylation reactions. The donation of a methyl group by SAM results in its conversion to s-adenosylhomocysteine (SAH), which, if accumulated, is a potent inhibitor of methyltransferases. MYC also enhanced the levels of alpha-ketoglutarate (αKG), a critical co-factor for histone demethylation mediated by Jumonji Domain-containing Histone Demethylases (JHDM). Thus, these results suggest that histone methylation processes may be severely hindered during MYC-driven prostate cancer progression. Again, this feature was further exacerbated by diet since increased SAH levels (higher SAH/SAM ratio) were observed in the VP of HFD-fed mice. Altogether, the data support the notion that HFD amplifies MYC-driven metabolic reprogramming.
High-Fat Diet Enhances Transcriptional Changes at H4K20me1 Dynamic Genes
To validate whether MYC/HFD affects histone methylation, researchers characterized 69 distinct combinations of histone modifications that span H2, H3, and H4 from all four genotype/diet combinations in all murine prostatic lobes (DLP, VP, AP) by using a targeted mass spectrometry approach. Unsupervised clustering of the different combinations of histone modifications revealed a strong MYC-driven signature in both DLP and VP. This was absent in the AP, in line with the marginal PIN penetrance observed in this lobe. Among the histone peptides monitored, H3K27/K36 and H4K20 were significantly affected by MYC overexpression. As previously described, MYC overexpression induced a steep decrease in H3K27me3 (corresponding to the H3K27me3K36meX peptides). In particular, the H3K27me3 mark was hypomethylated in a stepwise process that can be catalyzed by multiple JHDM enzymes and culminates with the unmethylated/acetylated H3K27 mark. A similar pattern was observed for the H4K20 mark, but in this case, the effect of MYC was significantly enhanced by HFD, leading to greater levels of the unmethylated mark. Importantly, HFD had no effect on the H4K20 mark in the WT tissues. H4K20me0 can be generated from H4K20me1, a mark that is associated with transcriptional elongation, by the JHDM enzyme PHF8. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) of H4K20me1 revealed highly dynamic levels of this mark along each gene body upon MYC overexpression with respect to the corresponding CTDWT reference. Interestingly, modulation of the H4K20me1 mark at the gene body dictates levels of gene expression: thus, loss of H4K20me1 is associated with a decrease, while gain of H4K20me1 is associated with an increase in gene expression. When comparing the gene expression levels for shared H4K20me1 dynamic gene body-associated regions between CTDMYC and HFD_MYC conditions, it was found that the MYC-effect was systematically enhanced by HFD. These results suggest that HFD further enhances MYC-driven H4K20 hypomethylation leading to transcriptional changes.
High-Fat Diet Enhances MYC Transcriptional Activity
To determine the cellular program specifically enhanced by HFD within a MYC context, Gene Sets Enrichment Analyses (GSEA) was performed using the Hallmark gene sets. As expected, MYC overexpression led to the enrichment of gene sets related to cell proliferation (E2Ftargets, G2Mcheckpoint), as well as MYC-transcriptional activity per se. Interestingly, HFD further enriched both gene sets related to MYC transcriptional activity (V1/V2), but only in MYC-transformed prostates. This feature was not linked to an increased expression of the MYC transgene. Because the MYC transcriptional program is highly context-specific, a murine prostatic MYC signature was generated by including the leading edge genes (n = 610) of MYC-related gene sets that were significantly enriched by MYC and/or HFD feeding. As expected, the expression levels of MYC signature genes were elevated following MYC overexpression and further increased by HFD. ChIP-seq of PHF8, the JHDM that mediates H4K20me1 demethylation and a known MYC transcriptional coactivator and regulator of proliferation, revealed that MYC overexpression increases the recruitment of PHF8 to the promoter regions of MYC signature genes. Again, this effect was enhanced by HFD. However, only when MYC overexpression was combined with HFD, was a significant decrease in H4K20me1 observed at PHF8 recruitment sites. Taken together, these results suggest that the observed HFD-induced enhancement of MYC transcriptional program is, at least in part, mediated via an increased recruitment and activity of PHF8 toward the H4K20me1 mark at MYC signature genes. This program then culminates in augmented cell proliferation and tumor burden.