Epigenetics is to blame
Why does visceral fat provoke the development of metabolic diseases
Anastasia Tsareva, PCR.news
The TwinsUK project — long-term studies of health and aging in a large cohort of twins — helped to find out why the accumulation of visceral fat contributes to metabolic disorders. In adipose tissue, the methylation of genes that play an important role in metabolism changes, in addition, this tissue ages faster.
Since 1975, the number of obese adults in the world has tripled, reaching 13%, and, apparently, will continue to grow. Obesity contributes to the development of type 2 diabetes, cardiovascular diseases and cancer. However, the molecular mechanisms of this dependence are not fully understood. To clarify this issue, an international team led by scientists from King's College London investigated the methylation of subcutaneous fat of the project participants TwinsUK.
GWAS studies have identified about 200 genetic variants associated with obesity, but they explain only 2-3% of the variability of this trait. The sharp increase in obesity suggests the influence of environmental factors, and they seem to be mediated by epigenetic mechanisms. Methylation levels are known to change with obesity. The authors emphasize that in such studies it is important to take into account not BMI, which does not distinguish between fat and fat—free mass, but the accumulation of visceral fat, that is, fat in the abdominal cavity, next to the liver, stomach and intestines, is a more significant risk factor.
Subcutaneous fat samples were taken from 538 female participants TwinsUK (average age 58.9 ± 9.5 years). It has previously been shown that the methylation signatures in subcutaneous and visceral fat are similar. The amount of visceral fat was assessed using X-ray densitometry. Methylation signatures were obtained for both fat and whole blood samples. Validation and repetition of the results were performed on 333 more individuals from three independent cohorts (USA, Denmark, Canada).
In the DNA of the samples, CpG positions were searched, which differed in methylation status in twins with different visceral fat weights, and 1,181 such positions were found in 788 genes. Interestingly, most of them were specific to adipose tissue and were not found in the blood.
An analysis combining epigenetics, genetics, gene expression, metabolomics, diet, and metabolic traits revealed positions in several genes strongly associated with metabolic diseases, including FASN, SREBF1, TAGLN2, PC, and CFAP410. Thus, methylation of the pyruvate carboxylase PC gene seems to mediate the effect of diet on visceral fat. (Pyruvate Carboxylase is the most important enzyme of the Krebs cycle.) Methylation of the FASN gene encoding the enzyme fatty acid synthase is more reliably associated with insulin resistance than BMI or visceral fat. Overall, FASN methylation was most strongly associated with metabolic health.
In addition, the authors used three well—known calculators of epigenetic aging - determining age by methylation status. It turned out that the accumulation of visceral fat is associated with accelerated biological aging. This is another possible way of visceral fat acting on metabolism and insulin resistance.
"It is important that we understand how increased body fat affects us at the molecular level and how this leads to the risk of metabolic diseases," said the head of the work, Dr. Jordana Bell. — Our study brings us one step closer to this goal: it identifies the epigenetic signature of excess belly fat, provides an understanding of its genetic and dietary triggers, and characterizes its functional effects and clinical implications for insulin resistance."
Article by Christiansen et al. Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers published in the journal Genome Medicine.
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