Links between one carbon metabolism and obesity

Recent findings have revealed how obesity may be linked with methylation, and how the diet may modify the pattern of DNA methylation, reports Gnosis SpA

In recent decades, the increasing global prevalence of obesity has become a major public health problem.1 An estimated 200 million adults in the US (or a staggering 68% of the adult population) are categorised as overweight or obese.

Obesity has become a significant contributor to rising healthcare costs in the country (total annual healthcare costs to treat obese adults now amount to nearly US$150bn). The condition is a leading cause of type 2 diabetes, disability, heart disease, morbidity and mortality, resulting in nearly 112,000 deaths in the US each year.2 Obesity is a multifactorial disorder in which lifestyle and environmental factors (such as dietary habits, sedentary behaviour and other environmental exposures) and genetics have a role. More specifically, in the last decade, there has been an increasing interest in the role of epigenetics in the development of this complex condition.3

The term epigenetics refers to modifications in gene expression that are controlled by heritable — but potentially reversible — changes in DNA methylation and/or chromatin structure, which are not accompanied by any DNA sequence changes.4–6 Epigenetic mechanisms constitute an essential mode of gene regulation and act as an interface between environmental exposures, cellular response and pathological processes, thereby determining whether or not the gene is active in a given cell at a given time.7

DNA methylation plays a key role in defining cellular identity and the differentiation of adipocytes. The study of DNA methylation profiles in different adipose tissue depots under different metabolic conditions could provide information about how the epigenetic regulation of adipose tissue is involved in the development of obesity and associated comorbidities, and how this could potentially be manipulated.8

Currently, we know that diet is one of the most studied environmental factors in epigenetic change.9 There is now mounting evidence to support the premise that nutrients may modify the pattern of DNA methylation. The most compelling evidence for nutrient-induced DNA methylation is related to folate because of its participation in one-carbon metabolism.10 One-carbon metabolism is a network of interrelated biochemical reactions that involves the transfer of single-carbon groups from one biological compound to another (methylation) and is essential for sustaining the life of cells.

Questions are now being asked about the possible role of folate and other nutrients involved in one-carbon metabolism in the manipulation of methylation status and obesity. In animal studies, the modification of DNA methylation by methyl donor supplementation has been shown to prevent transgenerational amplification of obesity in the well worked Agouti mouse model of genetic predisposition to obesity.11,12 Zhang recently evaluated the epigenetic modulation of DNA methylation by nutrition and its mechanisms in animals.13

The author describes three possible ways that nutrition influences DNA methylation patterns:

  • provision of substrates being necessary for proper DNA methylation
  • provision of cofactors modulating the enzymatic activity of enzyme involved
  • changing activity of the enzymes regulating the one-carbon cycle.

Importantly, all three mechanisms are mutually compatible and may operate together.13

As such, the universal methyl-donor for DNA, S-adenosylmethionine (SAMe), as well as active folate, may contribute to the right methylation pathway of the body. Nevertheless, as reported by the recent review in the International Journal of Obesity, significant progress has been made in the field of epigenetics and obesity, and there is still much to be learned before we fully understand the role of the epigenome in the development of this complex disease.2

References

1. www.who.int/gho/ncd/risk_factors/overweight/en/index.html, https://lifescienceintelligence.com/market-reports-page.php?id=A152.

2. S.J. van Dijk, et al., Int. J. Obes. (Lond.) 39, 85–97 (2015).

3. www.who.int/nutrition/publications/obesity/WHO_TRS_894/en/.

4. A. Bird, Genes Dev. 16, 6–21 (2002).

5. Y-H. Jiang, et al., Annu. Rev. Genom. Human Genet. 5(1), 479–510 (2004).

6. G. Lavorgna, et al., Trends Biochem. Sci. 29, 88–94 (2004).

7. S.W. Choi, et al., Adv. Nutr. 4, 530–532 (2013).

8. S. Gehrke, et al., PLoS ONE 8(12), e82516 (2013).

9. S. Altmann, et al., Brit. J. Nutr. 107, 791–799 (2012).

10. F.I. Milagro, et al., Mol. Aspects Med. 34(4), 782–812 (2013).

11. R.A. Waterland, et al., J. Nutr. 136, 1706S–1710S (2006).

12. S. Friso and S.W. Choi, J. Nutr. 132, 2382S–2387S (2002).

13. N. Zhang, Animal Nutrition: doi:10.1016/j.aninu.2015.09.002 (2015).

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