The prevalence of overweight and obesity has increased worldwide and is affecting millions of adults and children 1. The development of obesity is complex with factors like genetics, individual metabolism, dietary and physical activity choices, food and water availability, education and culture, playing a role 2. Several genome wide association studies have revealed an association between obesity and the gene encoding the transcription factor AP-2 beta (TFAP2B) 3,4. TFAP2B plays an important role during early stages of pregnancy in the development of different parts of the nervous system5. It has been demonstrated that overexpression of TFAP2B in fat cells causes a decrease in the production and release of adiponectin, a protein hormone which is involved in glucose metabolism6, and a diminished response to insulin7. But how does TFAP2B contribute to the development of obesity?
We have now shown in our ECPBHS study a very clear association between one TFAP2B variation (intron 2 VNTR) and measures of obesity and insulin resistance. Our findings have just recently published in the International Journal of Obesity8.
We found that men, who inherited the same variant of that gene from both parents (called 5/5 homozygotes), had significantly higher body weight, body mass index, proportion of body fat and insulin resistance, throughout adolescence to young adulthood. Strikingly, women that were 5/5 homozygotes had the same effects, but these appeared later, in young adulthood.
We hypothesized that the people who are TFAP2B 5/5 homozygotes have a higher risk of obesity because they consume more food. But we found the opposite: by age 25 male 5/5 homozygotes had smaller daily calorie intake and consumption of fats and carbohydrates. In females, these differences in caloric and macronutrient intake, were not observed. We therefor think that the risk is not related to increased food intake, but to differences in metabolism.
In conclusion, the gene TFAP2B increases the risk of obesity, abdominal obesity and insulin resistance in this sample, and is probably related to differences in metabolism. We should consider implementing lifestyle interventions already in childhood for individuals who are 5/5 homozygotes, to reduce the effect of TFAP2B on body weight. The physiological role of TFAP2B in body weight regulation and insulin resistance still needs further research.
- GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017; 377: 13-27. doi:10.1056/NEJMoa1614362
- Lee BY, Bartsch SM, Mui Y, Haidari LA, Spiker ML, Gittelsohn J. A systems approach to obesity. Nutr Rev. 2017; 75: 94-106. doi:10.1093/nutrit/nuw049
- Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015; 518: 197-206. doi:10.1038/nature14177
- Felix JF, Bradfield JP, Monnereau C, et al. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. Hum Mol Genet. 2016; 25: 389-403. doi:10.1093/hmg/ddv472
- Moser M, Rüschoff J, Buettner R. Comparative analysis of AP-2α and AP-2β gene expression during murine embryogenesis. Developmental Dynamics. 1997; 208: 115-124. doi:10.1002/(SICI)1097-0177(199701)208:1<115::AID-AJA11>3.0.CO;2-5
- Ikeda K, Maegawa H, Ugi S, et al. Transcription factor activating enhancer-binding protein-2beta. A negative regulator of adiponectin gene expression. J Biol Chem. 2006; 281: 31245-31253. doi:10.1074/jbc.M605132200
- Tao Y, Maegawa H, Ugi S, et al. The transcription factor AP-2beta causes cell enlargement and insulin resistance in 3T3-L1 adipocytes. Endocrinology. 2006; 147: 1685-1696. doi:10.1210/en.2005-1304
- Joost U, Villa I, Comasco E, Oreland L, Veidebaum T, Harro J. Association between Transcription Factor AP-2B genotype, obesity, insulin resistance and dietary intake in a longitudinal birth cohort study. Int J Obes [in press]. doi:10.1038/s41366-019-0396-y