Study Links Variants in 3 Genes Involved in Energy Expenditure to Severe Obesity

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by Vanessa Pataia |

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genetic variants and obesity risk

Variations in the PPARGC1A, UCP1, and FNDC5 genes — involved in regulating the body’s energy expenditure — are linked to severe obesity, a recent study suggests.

The study, “Genetic Variants in the Activation of the Brown-Like Adipocyte Pathway and the Risk for Severe Obesity,” was published in the journal Obesity Facts.

Energy expenditure, the amount of energy spent by the body to carry out essential functions, plays an important role in preventing obesity, particularly during exercise.

When a person exercises, the PPARGC1A gene, involved in regulating metabolism, is expressed at high levels in the skeletal muscles, which control movement.

The protein encoded by PPARGC1A, called PGC-1 alpha, is important for regulating the expression of other genes involved in energy production from fat and sugar (glucose). 

One of the roles of PGC-1 alpha is to increase the expression of the FNDC5 gene. After being produced, the FNDC5 protein is initially located at the cell membrane of muscle cells, and can be “cut” to originate a type of hormone called irisin, which is then released into the bloodstream. 

Irisin acts on fat cells to stimulate expression of the UCP1 gene. The resulting protein is involved in energy production, with some energy lost as heat.

Previous studies have found that genetic variations, called polymorphisms, in the PPARGC1A, UCP1, and FNDC5 genes may influence the risk of obesity and obesity-related traits. 

In the study, researchers in Brazil investigated if variants of the three genes could be associated with severe obesity and obesity-related traits in adults from Rio de Janeiro.

The study enrolled 210 adults with severe obesity, as evaluated by a body mass index (BMI) — a ratio of weight to height — of 35 or higher. The median BMI of participants with severe obesity was 45.6. Another 191 adults with normal weight (median BMI of 22.8) were also enrolled. The median age of all participants was 35 years.

Results showed that a PPARGC1A gene variant identified as rs2970847 (C) was associated with severe obesity. Individuals with this variant had nearly two times the risk of severe obesity compared to participants with a different gene copy.

According to previous studies, these types of genetic variations — which do not change the amino acid in the resulting protein — may disturb basic cellular processes with an effect on gene regulation, and both protein production and function. Amino acids are the building blocks of proteins.

A UCP1 gene variant identified as rs12502572 (A) was also more common in people with severe obesity. People who carried this particular variant had a 1.34 times higher risk of developing severe obesity.

The scientists suggested that this mutation might affect UCP1 gene expression and, consequently, energy expenditure but “functional studies are required” to clarify the link.

Carrying both the rs2970847 (C) and rs12502572 (A) variants had a greater effect than having either mutation alone, and was associated with greater body weight, BMI, and body adiposity index — an estimation of a person’s total body fat.

Data showed that another PPARGC1A variant, identified as rs8192678 (which changes glycine to serine, two amino acids), had an influence on blood glucose levels. 

According to researchers, this may be caused by the lower expression of this PPARGC1A gene variant, which leads to reduced levels of PGC-1 alpha protein. PGC-1 alpha protein stimulates muscle cells to take up glucose from the bloodstream and produce energy. So, the lower levels of PGC-1 alpha may have “resulted in decreased glucose uptake and metabolization,” the team wrote.

The investigators also identified five rare mutations in the FNDC5 gene, one of which had never been reported. This mutation also caused an amino acid change in the FNDC5 protein, from serine to asparagine. Computer analysis predicted this alteration to be disease-causing.

The scientists suggested that due to the involvement of irisin (produced from the FNDC5 protein) in energy expenditure, the novel mutation could “decrease energy expenditure and contribute to a susceptibility to severe obesity.”

Overall, the study shows that mutations in the PPARGC1A, UCP1, and FNDC5 genes “play an important role in the susceptibility to severe obesity,” the researchers concluded.

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