Abstract
Evaluation of: Wang X, Zhu H, Snieder H et al.: Obesity related methylation changes in DNA of peripheral blood leukocytes. BMC Med. 8, 87 (2010); Milagro FI, Campión J, Cordero P et al.: A dual epigenomic approach for the search of obesity biomarkers: DNA methylation in relation to diet-induced weight loss. FASEB J. 25(4), 1378–1389 (2011).
Obesity is characterized by excessive adiposity caused by a chronic, positive energy balance. In most cases, obesity is associated with a low-grade inflammatory state, with impaired leukocyte function and infiltration of nucleated blood cells at the site of insulin-sensitive tissues Citation[1,2], leading to metabolic impairments and Type 2 diabetes. There is a growing appreciation that environmental factors may alter DNA methylation, and thereby influence the gene expression that controls the metabolic memory of skeletal muscle and adipose tissue Citation[3,4]. Thus, epigenetic modifications through DNA methylation may contribute to the development of insulin resistance.
The immune system, largely because of its easy access to relevant cells, is one of the most frequently studied areas in the field of epigenetics. In healthy people, global DNA methylation in blood was shown to vary with age Citation[5,6]. In pathological states, notably in chronic kidney disease and cancer, the DNA methylation profile is altered Citation[7,8]. Alterations in inflammatory cytokines have also been associated with insulin resistance and obesity Citation[9]. Thus, the immune system may reprogram metabolically active tissues through epigenetic modifications that alter glucose and energy homeostasis in obesity and Type 2 diabetes.
Recently, Wang and colleagues have investigated the interindividual DNA methylation profiles of peripheral blood mononuclear cells from two separate cohorts of obese versus lean people Citation[10]. Using a CpG chip covering 27,000 CpG sites, a subset of genes that have an altered DNA methylation profile in obese patients were identified. The promoters of these genes were either hyper- or hypo-methylated, suggesting obesity has a gene-specific influence. Of the identified genes, the most statistically significant changes were found on the UBASH3A and TRIM3 genes, which were found to be hypermethylated and hypomethylated, respectively. In a larger, separate cohort of 91 individuals (14 were in the first cohort), UBASH3A and TRIM3 methylation levels were altered, but to a lesser extend. The span in the BMI between the lean and obese subjects in the second cohort of 91 individuals was narrower than that of the first cohort of 14 individuals. Moreover, the distribution in BMI was more heterogeneous in the larger cohort (30.5–59.9 kg/m2 in the obese group), which probably contributed to the smaller difference and higher statistical score between the analysis of the different groups. Nevertheless, the study of Wang and colleagues has highlighted the link between obesity and gene-specific DNA methylation changes in white blood cells. Whether the detected changes represent an epigenetic variation at the single cell level or generalized remodeling of the white blood cell subpopulation, remains to be determined. For instance, a previous report has provided evidence for a fivefold increase of CD34-positive cells in blood from obese individuals, suggesting that epigenetic changes could influence remodeling of the blood cell population Citation[2].
One exciting, but still underexplored area is the potential utility of epigenetic markers in the prediction of future disease susceptibility or resistance. Milagro and colleagues have touched upon this by highlighting the potential utility of epigenetic patterns as predictors of disease phenotype or disease prevalence related to energy homeostasis Citation[11]. These researchers determined the effect of an 8-week caloric restriction on CpG methylation in peripheral mononuclear blood cells in 25 overweight men. They identified responders to a caloric restriction and analyzed the DNA methylation status before and after the diet intervention to identify predictors of diet-induced weight loss. Before the dietary intervention, methylation on CpGs located in the region of ATP10A (also known as the ATPase class V) and CD44 correlated with changes in fat mass, as well as levels of the inflammatory cytokine TNF-α and the adipose-tissue-derived hormone leptin after calorie restriction. The authors suggest that these sites could be used as biomarkers for the prediction of diet-induced weight loss.
Further highlighting the role of inflammatory factors and the development of obesity, Milagro and colleagues identified differences in DNA methylation after weight loss, notably in TNFRSF9, ApoA-II and transforming growth factor Citation[11]. Irrespective of the response to calorie restriction, the genome-wide DNA methylation pattern was more homogeneous after (rather than before) the dietary intervention, suggesting that even though the caloric restriction affected body weight differently in individuals, it had a unifying effect on the epigenome. Nevertheless, the observed epigenetic variation could be a consequence of mononuclear subpopulation remodeling. Future studies designed to consider the use of methylation as a potential biomarker for the physiological response to weight loss should evaluate the possibility of a remodeling bias, so that tedious epigenetic testing procedures may be replaced by a simple blood formula.
The influence of epigenetic factors in the development of metabolic diseases such as obesity and Type 2 diabetes is a question of increasing interest. Future studies should consider the resolution of tissue-specific epigenomes and epigenetic responses in metabolic diseases or whether these marks are transgenerational. The answer to these questions is not trivial, but it will one day allow for an understanding of how environmental and genetic factors collectively influence susceptibility to metabolic disease.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Delamaire M , MaugendreD, MorenoM, Le Goff MC, Allannic H, Genetet B: Impaired leucocyte functions in diabetic patients. Diabet. Med.14(1) , 29–34 (1997).
- Bellows CF , ZhangY, SimmonsPJ, KhalsaAS, KoloninMG: Influence of BMI on level of circulating progenitor cells.Obesity (Silver Spring) (2011) (Epub ahead of print).
- Barres R , ZierathJR: DNA methylation in metabolic disorders.Am. J. Clin. Nutr.93(4) , 897S–900S (2011).
- Pinnick KE , KarpeF: DNA methylation of genes in adipose tissue.Proc. Nutr. Soc.70(1) , 57–63 (2011).
- Bjornsson HT , SigurdssonMI, FallinMDet al.: Intra-individual change over time in DNA methylation with familial clustering.JAMA299(24) , 2877–2883 (2008).
- Fraga MF , BallestarE, PazMFet al.: Epigenetic differences arise during the lifetime of monozygotic twins.Proc. Natl Acad. Sci. USA102(30) , 10604–10609 (2005).
- Stenvinkel P , KarimiM, JohanssonSet al.: Impact of inflammation on epigenetic DNA methylation – a novel risk factor for cardiovascular disease?J. Intern. Med.261(5) , 488–499 (2007).
- Marsit CJ , KoestlerDC, ChristensenBC, KaragasMR, HousemanEA, KelseyKT: DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer.J. Clin. Oncol.29(9) , 1133–1139 (2011).
- Austin RL , RuneA, BouzakriK, ZierathJR, KrookA: siRNA-mediated reduction of inhibitor of nuclear factor-κB kinase prevents tumor necrosis factor-α-induced insulin resistance in human skeletal muscle.Diabetes57(8) , 2066–2073 (2008).
- Wang X , ZhuH, SniederHet al.: Obesity related methylation changes in DNA of peripheral blood leukocytes.BMC Med.8 , 87 (2010).
- Milagro FI , CampiónJ, CorderoPet al.: A dual epigenomic approach for the search of obesity biomarkers: DNA methylation in relation to diet-induced weight loss.FASEB J.25(4) , 1378–1389 (2011).