Epigenetic modification which raises obesity risk and predicts fatty liver identified.


Obesity has become a major health threat, affecting more than half a billion people worldwide in 2014.  In particular, obesity increases the risk for insulin resistance, hypertension, coronary heart disease and type 2 diabetes. The risk of obesity is largely influenced by the family background, indicated by heritability rates of up to 40% for body mass index. However, genetic variants identified so far only explain less than 5% of the observed heritability, a phenomenon referred to as ‘missing heritability’.  This discrepancy suggests that other hereditary factors also play a role, such as epigenetic changes in the genetic material.

These epigenetic modifications do not change the genetic code, and may contribute to the inhibition of gene expression, or cause cells to produce smaller amounts of the corresponding proteins. This can lead to metabolic disorders, among other disturbances which may also be inherited. Recent studies increasingly suggest that diet as an environmental factor can affect the activity of genes via chemical modification, or methylation, of the DNA nucleotides.  Now, a study from researchers led by the German Institute of Human Nutrition (DIfE) shows in a mouse model that the epigenetic modification of the Igfbp2 gene observed in the young animal precedes a fatty liver in the adult animal later in life. The team state that their findings also show young animals with this modification exhibit impaired glucose metabolism and are significantly more prone to morbid obesity and were able demonstrate this modification in the corresponding gene in morbidly obese people with incipient diabetes.  The opensource study is published in the journal Human Molecular Genetics.

Previous studies showed that people who suffer from type 2 diabetes and fatty liver produce lower amounts of the protein IGFBP2 in the liver. At the same time the group was able to demonstrate that the reduced IGFBP2 secretion is accompanied by an increased rate of DNA methylation of various genes. The current study investigates the extent to which the reduced protein secretion is due to epigenetic changes, in the C57BL/6J mouse-model.

The current study utilised a mouse-model where all animals of this strain are genetically identical. Results show that  some mice gained much more weight than others when given a high-fat diet and developed a fatty liver. Data show that already at the age of six weeks the Igfbp2 gene exhibited higher levels of methylation, or stronger epigenetic modification, with IGFBP2 synthesis in the liver significantly reduced.

The lab observed that the mice first showed disturbances in glucose metabolism very early, with further studies demonstrating that methylation in the non-coding region of the Igfbp2 gene contributes to less IGFBP2 synthesis. The group note that they detected the same epigenetic modification in the human-equivalent of the Igfbp2 gene in patients suffering from morbid obesity and whose glucose metabolism was already disturbed.

The team surmise that their findings indicate the epigenetic modification makes both mice and humans more susceptible to obesity and raises their risk of developing a fatty liver with increasing age. For the future, the researchers state that since methylation of the gene already occurs very early, well before a fatty liver has developed, it would be conceivable to use this knowledge to better assess the disease risk in adolescents and young adults.  They go on to conclude that with appropriate measures, disease could thus be prevented in time.

Source: German Center for Diabetes Research (DZD)

 

DNA methylations occur when methyl groups bind to the DNA. These can either activate or inactivate genes. Epigenetic factors modify histone tails by e.g. transferring methyl or acetyl groups on lysine side chains. This can complicate or facilitate the activation of a gene. The direct methylation of the DNA changes the gene expression permanently if it takes place in the control regions of genes (so-called CpG islands), that have been made accessible by the modification of the histones.  Credit: Copyright: DIfE.

DNA methylations occur when methyl groups bind to the DNA. These can either activate or inactivate genes. Epigenetic factors modify histone tails by e.g. transferring methyl or acetyl groups on lysine side chains. This can complicate or facilitate the activation of a gene. The direct methylation of the DNA changes the gene expression permanently if it takes place in the control regions of genes (so-called CpG islands), that have been made accessible by the modification of the histones. Credit: Copyright: DIfE.

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