Scientists may have pointed to a new approach in the treatment of obesity with the discovery of genetic mutation responsible for obesity in mice. In a study published in New England Journal of Medicine on April 14, 2016, Dr Dalgaard et al attempted to explain the genetic variant – called Trim28 – that links the environmental factors with the gene expression and causes obesity.
We all know that obesity can be inherited but what we did not know until now was that environmental factors could literally “switch on” the gene responsible for inherited obesity, thanks to Dr Dalgaard and his new study.
In the recent study, Dr Dalgaard and colleagues characterized mice on the basis of mutation in the gene encoding Trim28 — tripartite motif-containing 28. Trim28 is a protein in human body that is present in the gene called Trim28 gene. This protein is a member of tripartite motif family and is present in the nucleus. It mediates transcription – first step in the gene expression where a segment of DNA is converted into RNA by the enzyme RNA polymerase. Basically transcription is a process where part of the DNA replicates and new protein is formed in the body.
Trim28 – a zinc-finger transcription factor – is responsible for transcription repression. It means that mutation in one copy of Trim28 affects the obesity distribution that can be triggered “on and off” by certain environmental factors.
Back to the study where Dr Dalgaard studied the body mass index (BMI) and gene expression in mice. The researchers noticed that the average weight gain in the obese mice – termed “on” – was due mainly to the distribution of adipose tissue – loose connective tissue in the body that stores fat. The average weight gain in this phenotype group was approximately seven grams. On the contrary, the weight gain was minimal or nonexistent in the other group of mice that was lean and termed “off”.
Dr Dalgaard and team noticed that the doubling of the number of adipocytes – fat-storing cells – in the obese mice (on) accounted for the doubling of adipose-tissue mass.
Up until now, the researchers could see a pattern i.e., the mice were obese when Trim28 was “on”, thin when Trim28 was off. All mice were Trim28 littermates.
However, what was puzzling was the mechanism for the storage of adipose tissue in the obese mice. Researchers noticed a change in behavior in these mice that appeared anxious, stressed and sluggish which hinted a link between the brain and the “on” state of the animal.
To dig into the question and find the answer, the researchers studied the gene-expression profiles of the fat-storage tissues in obese and non-obese mice. The findings were compared with the gene-expression profiles from the wild-type mice that were divided into two groups – one was fed high-fat diet; the other regular chow. The researchers noticed little or no correlation between the differences implicating that obesity caused by overeating and low-expression of Trim28 had different mechanisms.
While executing the study, the prime focus of the researchers were the genes that were down-regulated, some of which are responsible for height and weight. Down-regulation is a process in which the cell reduces its cellular components as a result of exposure to an external stimulus. Upregulation is an increase in the cellular components. And during the study, they found nine sets of imprinted genes and one imprinted gene network (IGN1) to show differences in expression in mice.
However, the researcher noticed no difference in DNA-methylation of these genes.
In an attempt to isolate the bimodal (on-off) cause of obesity distribution, the researchers removed a cluster of IGN1 genes in a subgroup of mice. Removal of two specific genes from the cluster i.e., Peg3 and Nnat, exhibited an “on” phenotype. This formed a substantial evidence for the epigenetic regulation of the bimodal obesity distribution.
The scientists concluded that “dysregulation of imprinted genes was responsible for the Trim28-dependent bimodal obesity in the mice”.
The big question now is whether these findings can be replicated in humans. Polyphenism exists in humans as well. The authors of the publication obtained suggestive data in humans and studied Trim28 expression and its relation to adiposity. The findings showed that people with low levels of Trim28 exhibited IGN1 dysregulation and were more likely to be obese than people with high levels of Trim28 expression.
This finding is in line with the current observation in mice. However, not much about regulation of Trim28 expression in humans is known. Further research on the possible contribution of phenotypes to human obesity endemic is needed. If it is proven that environmental factors can “switch on and off” the gene responsible for obesity, a way to manipulate these factors may then be devised to control obesity.
Obesity is a highly prevalent condition affecting about half a billion people in the world. Obesity is not a disease per se, but increases the risk for many diseases including cardiovascular problems, cancer and diabetes. Heredity (DNA) and environmental factors play a big role in controlling the adiposity.