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Obesity findings set precedent for GWAS research

7 September 2015
Appeared in BioNews 818

BioNews recently reported on the discovery of a mechanism explaining how certain genetic variants are linked to obesity (see BioNews 816).

The study, published in the New England Journal of Medicine, found that the presence of a particular DNA bases within the FTO gene makes a person's adipose cells less likely to burn energy, and more likely to store it as fat.

The findings, which made use of a remarkable suite of genomic and experimental tools, not only revealed a molecular mechanism that contributes to obesity, but they are also an exemplar of how genome-wide association study (GWAS) findings can make the journey to clinical relevance.

There are numerous controversies and confusing results in obesity research, and heritability is no exception. Many studies have identified that obesity is heritable, at least to some extent, with the presence of certain genetic variants being more common in people with higher body mass indexes (BMIs).

The FTO gene has repeatedly been identified in GWASs as the most significant genetic location to associate with obesity and higher BMI scores. While such findings don't explain all of the variability we see in how much people weigh (the so-called 'missing heritability' of obesity), exploring the involvement of the genome with determining someone's propensity to lose or gain weight stands to offer widespread medical gains.

In previous studies, obesity-linked variants in FTO have been proposed to affect body size in a number of ways, such as one previous idea which claims that the FTO protein itself – expressed in the brain – might influence obesity by influencing appetite (see BioNews 714).

However, as genetic variants in the FTO gene do not encode different protein sequences it has remained unclear exactly how they might influence a person's physiology. The authors of this recent paper performed a large number of experiments to try to find out what these genetic variants were doing, in which tissues, and how this could influence body size.

They first made use of epigenomic data, which describes the variety of heritable chemical modifications which occur across the genome, influencing which sections of DNA are active at any one time in a particular cell. This highlighted FTO gene activity in developing fat cells called pre-adipocytes.

The researchers then extracted pre-adipocyte cells from a group of 100 Europeans, half of whom carried the obesity-associated risk variants, and half of whom didn't, and measured their gene expression.

They found that those with the risk variants had greater expression of two genes – IRX3 and IRX5 – than those without. The activity of these two genes, in turn, appears to determine what type of fat cell a pre-adipocyte becomes: increased expression of IRX3 and IRX5 makes pre-adipocytes less likely to develop into energy-burning beige cells, and more likely to turn into lipid-storing white fat cells.

In follow-up experiments, using CRISPR/Cas9 technology, the researchers were able to show, by changing a single nucleotide, that substituting the 'healthy' variant for the risk-variant in cells taken from participants, caused cells to decrease IRX3 and IRX5 production and behave more like beige cells, increasing thermogenesis and decreasing lipid storage.

'Early studies of thermogenesis focused primarily on brown fat, which plays a major role in mice, but is virtually nonexistent in human adults. This new pathway controls thermogenesis in the more abundant white fat stores instead, and its genetic association with obesity indicates it affects global energy balance in humans,' first author Dr Melina Claussnitzer said of the results.

It will take further studies to test opposing models to see which hold up under scrutiny – although multiple models could indeed be true. This study however represents a colossal amount of technically challenging experimental work, from a variety of different scientific disciplines, with an impressive number of validation experiments, which bodes well the for accuracy of these results.

Genetic modulation, as was performed in this study, is currently not a viable option for the treatment of obesity, and so this study might not directly offer any immediate clinical opportunities. However it presents a number of interesting scientific breakthroughs and could influence weight-management by other means.

'Knowing the causal variant underlying the obesity association may allow somatic genome editing as a therapeutic avenue for individuals carrying the risk allele,' author Dr Manolis Kellis said. 'But more importantly, the uncovered cellular circuits may allow us to dial a metabolic master switch for both risk and non-risk individuals, as a means to counter environmental, lifestyle, or genetic contributors to obesity.'

The research underlines the importance of beige fat and thermogenesis in regulating body weight, and highlights a particular pathway by which this occurs in certain cells.

Moreover, it is a thorough demonstration of how genetic markers can predispose an individual to fat retention, which is especially relevant in populations like Europeans in whom these risk-associated alleles are relatively common (found in 44 percent of individuals, compared to five percent in African populations).

Perhaps most importantly, it provides a rationale by which the causal biological processes of other single nucleotide differences revealed by GWAS can be investigated, opening the doors to new insights in the wide array of medical conditions which have risk-associated genetic variants.

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