Cardiometabolic disease (CMD) is a term used to define risk factors associated with the development of diabetes and cardiovascular disease. One major characteristic which contributes to these risk factors is obesity. Worldwide, obesity has nearly doubled since 1980 and in 2008, more than 1.4 billion adults 20 and older were overweight (1). Additionally more than 40 million children under the age of five were overweight in 2011 (1). Childhood obesity is associated with a higher chance of obesity, premature death and disability in adulthood (1).
While environmental influences play a significant role in contributing to being overweight and obese, genetics and epigenetics may also be involved in the development of these conditions. In particular, DNA methylation is an epigenetic modification which can alter the expression of genes involved in fat/energy metabolism by turning them “on” or “off”.
Peroxisomal proliferator-γ-co-activator-Iα (PGC-1α) is one such gene which codes for a protein involved in energy/fat metabolism. PGC-1α is a transcription co-activator that interacts with a broad range of transcription factors that are involved in a wide variety of biological processes including adaptive thermogenesis, mitochondrial biogenesis and glucose/fatty acid metabolism (2). Reduced PGC-1α activity has been linked to an increased risk of Type 2 diabetes (T2D) and therefore may play a role in preventing this disease (3).
To investigate whether methylation of PGC-1α may be used as a marker in predicting risk of CMD, scientists at the Universities of Southampton, Exeter and Plymouth in the UK performed a cohort study of 40 children from age five over a nine year period. Annually the children were assessed for physical changes physical fitness as well as for DNA methylation changes at seven sites of PGC-1α.
Previous studies have reported that these sites tend to be methylated in overweight adults with T2D compared with average weight adults (4). The effect of methylation on transcription factor binding was investigated by electrophoretic mobility shift assay. Their results suggest that methylation at temporarily stable CpG loci of PGC-1α may be useful in predicting CMD risk. In addition, being overweight or obese in childhood may not only be due to lifestyle but to how our genes are regulated.
Their findings are summarized below:
- The level of methylation at the seven loci of PGC-1α was relatively stable over the nine year study period.
- For one locus a 10% increase in DNA methylation levels at five years of age was associated with up to 12% more body fat at age 14.
- Generalized estimate modeling equations showed that methylation at four of the seven loci predicted adiposity up to 14 years. This finding was independent of gender, level of physical activity or time of reaching puberty.
- Methylation of one locus modified binding of the pro-adipogenic PBX-1/HOXB9 complex.
Read more about their findings and get all of the details here: Clarke-Harris R., et al, Peroxisomal proliferator activated receptor-γ-co-activator-1α promoter methylation in blood at 5-7 years predicts adiposity from 9 to 14 years (EarlyBird 50) Diabetes. 2014 Mar 12. [Epub ahead of print].
1) World Health Organization (2013, March) Obesity and overweight. Retrieved from http://www.who.int/mediacentre/factsheets/fs311/en/
2) Liang H. and Ward WF. PGC-1α: a key regulator of energy metabolism. Adv Pysiol Educ (2006), 30: 145-151.
3) Hara K, Tobe K, Okada T, Kadowaki H, Akanuma Y, Ito C, Kimura S, and Kadowaki T. A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes. Diabetologia (2002), 45: 740–743.
4) Ling C, Del Guerra S, Lupi R, Ronn T, Granhall C, Luthman H, Masiello P, Marchetti P, Groop L, Del Prato S. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia (2008), 51:615-622.