| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
LETTER TO THE EDITOR |
MRC Centre for Causal Analyses in Translational Epidemiology
Department of Social Medicine
University of Bristol
Canynge Hall
Whiteladies Road
Bristol
United Kingdom
E-mail: d.a.lawlor{at}bristol.ac.uk
E-mail: george.davey-smith{at}bristol.ac.uk
Department of EpidemiologyPublic Health
University College London
1-19 Torrington Place
London WC1E 6BT
United Kingdom
E-mail: m.kivimaki{at}ucl.ac.uk
Dear Sir:
Cole et al suggest that genomic imprinting could result in equivalent parental prenatal influences on offspring body mass index (BMI) or obesity, although they acknowledge that "how genomic imprinting might operate to equalize parental influences is as yet a mystery...". We agree with this latter point.
According to the fetal overnutrition hypothesis, exposure of the developing fetus to high glucose and free fatty acid concentrations (from the mother's circulation) results in permanent changes in appetite control, neuroendocrine functioning, or energy metabolism in the developing fetus, which leads to greater adiposity and risk of obesity in later life (1-3). Strong evidence for this maternal hypothesis comes from the association of maternal gestational hyperglycemia with offspring adiposity. Maternal gestational diabetes is associated with later offspring obesity (1, 4), and there is some evidence of a graded association across maternal distributions of fasting and postload glucose during pregnancy with offspring obesity risk at ages 5–7 y (5). The notion that this represents a maternal intrauterine mechanism is elegantly demonstrated by research among the Pima Indians of Arizona—a group at high risk of obesity and diabetes. A marked excess in the risk of obesity was found in offspring (assessed up to age 20 y) born to mothers who had diabetes during their pregnancy compared with either the offspring of mothers who developed diabetes later in their lives (but were nondiabetic in pregnancy) or those who never developed diabetes (risk of offspring obesity was similar in these 2 latter groups) (4, 6). In a small nuclear family study (52 families, 182 siblings), also conducted in the Pima Indian population, obesity was greater among nondiabetic offspring born after type 2 diabetes was diagnosed in the mother (ie, exposure to increased intrauterine glucose concentrations) than in their siblings born before their mother's diagnosis (ie, exposure to lower intrauterine glucose concentrations) (4, 7). In an elegant control it was shown that the same was not true with respect to whether the offspring were born before or after the diagnosis of diabetes in their fathers (7).
An extension of the fetal overnutrition hypothesis suggests that greater maternal adiposity might act through similar intrauterine mechanisms and might be an important driver of the obesity epidemic (8). Because greater maternal adiposity is associated with a greater risk of insulin resistance and glucose intolerance, mothers who are more obese at the time of their pregnancy will have higher concentrations of glucose and free fatty acids, and the offspring of these mothers would be expected to be programmed to become more obese themselves. The consequences of this hypothesis (if true) are important: "the obesity epidemic could accelerate through successive generations independent of further genetic or environmental factors" (8). In our recent article in the Journal (9) and in other recent articles (10-12), we have sought specifically to address this question, ie, whether via a specific intrauterine effect, greater maternal adiposity during pregnancy results in greater offspring adiposity.
A positive association between maternal BMI and offspring BMI could be explained by fetal overnutrition, but could also be explained by the simple inheritance by the fetus of their mother's adiposity-related genes or by shared familial lifestyles related to adiposity. We argued that genetic inheritance and shared familial environment are mechanisms likely to act similarly with respect to mothers and fathers, whereas fetal overnutrition is by definition a maternal-specific effect (9-12). Thus, similar associations of maternal BMI with offspring BMI to that of paternal BMI with offspring BMI would support mechanisms likely to be similar for mothers and fathers (genetic inheritance and shared familial lifestyle/obesogenic environment).
The implication of Cole et al's correspondence is that genomic imprinting could produce a paternally mediated prenatal effect that would closely match in size that of any maternal overnutrition effect. Although it is possible that male-line epigenetic factors exactly mimic a biological influence of maternal obesity and a consequent greater delivery of glucose, free fatting acids, and amino acids on the intrauterine environment to generate very similar associations, we feel this is unlikely. Informal or formal approaches to comparing explanatory models, which adopt the parsimony principle of Occam's Razor (13), suggest that the likelihood of such perfectly mimicked effects, when they are produced by mechanistically completely distinct effects, is rather low.
Cole et al seem to only consider prenatal and postnatal environmental influences as explanations for the intergenerational association of BMI or obesity. It seems likely to us that genetic inheritance is one mechanism contributing to this association, although, as discussed in our article, germline genetic factors are clearly not an explanation for the increases in BMI and obesity prevalence across generations (9). In addition to examining the fetal overnutrition hypothesis in the Young Finns cohort, we have compared maternal to paternal BMI associations with offspring adiposity in 2 additional populations (10-12). In an Australian birth cohort there was a weak, but consistent, stronger association of maternal BMI with offspring BMI than of paternal BMI with offspring BMI (11). In the UK Avon Longitudinal Study of Parents and Children, associations were equivalent (as they were in the Young Finns cohort) when offspring BMI was the outcome of interest (10), but there was a consistently (though weak) stronger association of maternal BMI with offspring fat mass (12). Furthermore, in the latter study, in which we used maternal FTO genotype as an instrumental variable for her adiposity, there was no strong evidence of maternal adiposity being associated with offspring adiposity other than by genetic inheritance or shared familial environment (12). Taking this evidence together we conclude that intrauterine mechanisms linking maternal adiposity to offspring adiposity are unlikely to have been a major driver of the recent obesity epidemic (12).
We agree with Cole et al that much remains to be learned about epigenetic effects on growth. However, we suspect that in terms of public health this will also fail to be a major driver of the obesity epidemic and that public health interventions related to diet and exercise in individuals and families will remain the key requirements to tackle high levels of population obesity.
ACKNOWLEDGMENTS
No conflicts of interest were reported.
REFERENCES
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
