Monday, April 25, 2011

Epigenetics - From Mother to Child: Retinoid X Receptor-α Methylation "May Explain >25% of the Variance in Childhood Adiposity"

A few blogposts "ago", I reported the negative influences maternal (over-)nutrition may have on the unborn child. A recent study (Godfrey. 2011) from the University of Southampton provides insights into which detrimental genetic switches underlie a disadvantageous pre-natal metabolic programming, the consequences of which may well be one of the myriad of factors contributing to the global increase in (childhood) obesity.
Figure 1: Rise in childhood obesity from 1963-2008 (from

Godfrey et al. analyzed the methylation status (if a gene is methylated it is turned off) of several genes in the cord blood of newborns from two independent cohorts (cohort 1: 68 samples; cohort 2: 31 samples) and found that
[i]n cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95%CI 4-31], P = 0.009, n = 64, and β = 20% [9-32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1-19], P = 0.023, n = 64 and β =12% [4-20], P = 0.002, n = 66, respectively).
Furthermore, additional statistical analyses revealed that [in cohort 1] these “epigenetic marks explained >25% of the variance in childhood adiposity”.

While the correlation with eNOS, which was found in cohort 1, could not be established in the second cohort, the correlation between retinoid X receptor-alpha methylation and childhood obesity [measured at the age of 9 years] was observed (to a lower degree, β(BodyFat%)=4%) in cohort 2, as well. The exact mechanism, by which these nuclear receptors, which mediate the biological effects of retinoids on our bodies, influence the deposition of body-fat, is still not completely elucidated, the activation of PPAR-gamma, which by itself has attracted some attention as a potential target for treatment strategies for the metabolic syndrome, could yet play a major role.
Figure 2: Exponentiated regression coefficients β of retinoid X receptor-α (RXRA) and endothelial nitric oxide synthase (eNOS) methylation with body fat % of children at the age of 9 years.
(data adapted from Godfrey. 2011)
Interestingly, and for some of you certainly counter-intuitively, the latter, i.e. the methylation of RXRA  correlated positively with a low carbohydrate intake. This would mean that a low maternal carbohydrate intake, of which Goldrey et al. claim that it had been "previously linked with higher neonatal adiposity in this population", would increase the risk of childhood obesity via epigenetic programming of the offspring. I would however question, in how far the latter assumption, i.e. 'maternal low carb diet = fat children', may be based on unreliable data from studies, in which the "traditional" UK fish & chips diet was considered "low carb" if one replaced half of the chips with bacon and sausages was equated with a "low carbohydrate intake"

On a side note: If you are interested in the question how reliable scientific "data" (which is by no means, as the name /lat. dare = to give/ would imply, "given" to us) actually is and have not yet listened to my latest appearance on Carl Lenore's Super Human Radio, where I discuss some factors to consider, when you look at the data from scientific studies, I suggest you go and download the podcast ;-)