A variant of the TFAP2B gene is associated with the development of obesity and insulin resistance from adolescence into young adulthood, a large study of schoolchildren in Estonia found.
The effect is present in males in their teenage years but emerges later in females, during young adulthood, and is probably linked to differences in metabolism rather than energy intake.
The study, “Association between Transcription Factor AP-2B genotype, obesity, insulin resistance and dietary intake in a longitudinal birth cohort study,” was published in the International Journal of Obesity.
While a large variety of genes appear to play a role in determining an individual’s weight, the debate continues over the contribution of genes and environment compared to differences in food intake, physical activity and body mass index (BMI).
Recent studies found a link between variations within the TFAP2B gene and a tendency for larger BMI and obesity. Large-scale genome-wide association studies (GWAS) in adults of European and non-European descent found a link between BMI variation and 97 genetic regions, or loci, including TFAP2B. Similar results were found in association studies exploring genetic risk factors for obesity in children. TFAP2B is also associated with type 2 diabetes.
TFAP2B provides cells with instructions for making a protein called transcription factor AP-2β. A transcription factor is a protein that binds to specific regions in DNA, and helps control the activity of specific genes that, in turn, affect the working of certain biological processes.
Transcription factor AP-2β was seen to participate in the metabolism of adipocytes (fat cells) by facilitating sugar uptake and fat accumulation, while increasing resistance to insulin — a driving factor that can lead to type 2 diabetes, gestational diabetes, and prediabetes.
An earlier work identified a genetic variation, or polymorphism, of TFAP2B that was associated with abdominal obesity and insulin resistance in 15-year-old boys. Some people carry a 5-repeat (a small DNA sequence repeated five times in a row) in the gene while others carry a 4-repeat.
Because a person inherits two copies of each gene, one from each parent, some people may carry a 5-repeat inherited from one parent and a 4-repeat from the other. These people are referred to as heterozygotes. People who carry two copies of 5-repeat or two copies of a 4-repeat are called homozygotes.
To shed light on this association and how it develops over time, researchers examined the relationship between TFAP2B 5-repeat and obesity, insulin resistance, and dietary habits among 1,176 children living in Estonia, who were followed from ages 15 to 33.
Anthropometric measurements (height, weight, BMI, waist, and hip circumference), blood pressure, laboratory tests, and insulin resistance (defined using the HOMA index based on fasting blood sugar and insulin levels) together with dietary intake were assessed at ages 15, 18, and 25. Tests were also conducted at age 33 with some participants.
Results showed that males homozygote for the 5-repeated variant (two copies) weighted significantly more and had a higher BMI, body fat percentages, and insulin resistance compared to heterozygotes (one copy of the 5-repeat, and one of copy of the 4-repeat) from ages 15 through to 25.
At age 33, male homozygotes weighted 6.78 kg more and had 2.23% more of fat, on average, than heterozygotes. Similar trends were observed at age 15 and 18.
This difference was even greater when compared to homozygotes for the 4-repeat; that is, compared to young people who did not carry any 5-repeat copy. Male 5-repeat homozygotes weighed 10.28 kg more and 4.4% more body fat at age 33 than the 4-repeats.
An identical association was not apparent at any age in females, suggesting that the effects of TFAP2B 5-repeat take place earlier in life.
However, a higher rate of yearly increases in body weight and BMI in female 5-repeat homozygotes was noted, compared to female heterozygotes between 15 and 25 years old.
“Overall, the results strongly support the notion that TFAP2B plays an important role in the development of obesity and abdominal obesity. We have also demonstrated that the effect … on anthropometric measures and glucose metabolism differs between male and female subjects,” the researchers wrote.
In females, the effect of TFAP2B on obesity appears in young adulthood. The effect is rather related to differences in metabolism rather than energy intake (calories).
The reason why TFAP2B seems to influence obesity and insulin resistance, and the cause for sex differences seen, remains unclear.
There is evidence that males are more prone to eat in the absence of hunger, and females are more likely to make better dietary choices. Metabolic differences between sexes are also well-established.
However, it is unlikely that the TFAP2B effect depends on food consumed, as heterozygotes — rather than homozygotes — had a similar or greater daily caloric intake per year. Other factors, such as differences in metabolism, are more likely to be involved.