Dr. Sharma's Obesity Notes

Readers of these pages are by now quite familiar with the increasing evidence showing that what happens to the fetus in utero may be a key determinant of obesity risk later in life. Thus, both small-for-gestational-age and large-for-gestational-age babies appear at increased risk for becoming obese kids (and adults).

One of the important determinants of infant weight is the magnitude of maternal weight gain in pregnancy. But how strong is this relationship really?

This question was now examined by David Ludwig (Harvard) and Janet Currie (Columbia) in a paper published last month in The Lancet.

The researchers examined data from a population-based cohort study that included all known births in Michigan and New Jersey, USA, between Jan 1, 1989, and Dec 31, 2003, or a total of 513 501 women and their 1,164,750 offspring.

Using a within-subject design to reduce confounding to a minimum, they noted a strong and consistent association between pregnancy weight gain and birthweight: infants of women who gained more than 24 kg during pregnancy were almost 150 g heavier at birth than were infants of women who only gained 8-10 kg.

Women who gained more than 24 kg during pregnancy were more than twice as likely to give birth to an infant weighing more than 4000 g than women who only gained 8-10 kg.

In light of the increasing evidence that larger infants are much more likely to become overweight and obese children (and later adults), this study certainly supports the need for efforts to prevent excessive weight gain during pregnancy.

Targeting obesity prevention and treatment strategies to younger women and limiting excessive weight gain during pregnancy, may well be the single most effective way to prevent obesity in future generations.

AMS
Edmonton, Alberta

Ludwig DS, & Currie J (2010). The association between pregnancy weight gain and birthweight: a within-family comparison. Lancet, 376 (9745), 984-90 PMID: 20691469

Regular readers will recall the many posts on the issue of intra-uterine epigenetic programming, that is now believed by many to be one of the key drivers of the childhood obesity epidemic.

As more and more human and experimental evidence for this hypothesis accumulates, it is becoming increasingly evident that the intra-uterine environment may play a central role in determining the future risk of obesity in offspring (even much later in life).

This notion is further supported by an interesting study by Ricardo Orozco-Solís and colleagues from the Université de Nantes, France, published in the latest issue of PLoS One, showing that in rats, maternal nutrition during pregnancy is linked to long-lasting changes in nutrient sensing and energy homeostasis in the hypothalamus (the brain centre that regulates eating behaviours).

In this study, the researchers analyzed the profile of the hypothalamus transcriptome (the sum of all genes expressed as RNAs) in 180 days-old rats born to dams fed either a control (200 g/kg) or a low-protein (80 g/kg) diet through pregnancy and lactation.

From the almost 30,000 examined genes, around 700 were up-regulated and 300 down-regulated by early protein restriction.

Most interestingly, the researchers found that perinatal protein restriction permanently altered the expression of two gene clusters regulating a large number of common cellular processes.

While the first gene cluster includes several gate keeper genes regulating insulin signaling and nutrient sensing, the second cluster represents a functional network of nuclear receptors and co-regulators of transcription involved in the detection and use of lipid nutrients as fuel. This network also links temporal and nutritional cues to metabolism through their tight interaction with the circadian clock (in this context readers may recall the recent posts on the link between sleep and obesity).

As pointed out by the authors, these findings clearly show that (protein-) malnutrition during pregnancy and lactation may play a key role in epigenetically programming hypothalamic circuits regulating energy homeostasis.

As blogged before, the key to preventing childhood obesity may well lie in ensuring maternal nutrition and healthy body weights - once born, as with the proverbial horses, the kids may be out of the barn!

AMS
Hamilton, Ontario

Orozco-Solís R, Matos RJ, Guzmán-Quevedo O, Lopes de Souza S, Bihouée A, Houlgatte R, Manhães de Castro R, & Bolaños-Jiménez F (2010). Nutritional programming in the rat is linked to long-lasting changes in nutrient sensing and energy homeostasis in the hypothalamus. PloS one, 5 (10) PMID: 20975839

One of the most exciting and biologically highly plausible reasons for the childhood obesity epidemic may well be that current generations are far more susceptible to obesity because of “epigenetic programming”.

Simply put, the notion is that exposure to an adverse fetal environment, as in the case of maternal obesity, diabetes or hypertension during pregnancy, can lead to a lifelong change in the genetic program of the offspring, making them genetically more prone to obesity.

Thus, although the children are born with the same genetic code as their parents, whether or not certain genes are “more” or “less” active, is determined by the fetal (and possibly early post-natal) environment.

While these “epigenetic” changes are well documented in animal studies, exactly which genes are affected in the context of intergenerational transmission of obesity is not clear.

A study by Luigi Bouchard and colleagues from Université de Montréal, Canada, just published online in Diabetes Care, suggests that one of the modified genes may well be leptin, a key regulator of energy balance.

The researchers examined placental tissues as well as maternal and cord blood samples from 48 women, 23 of who had gestational impaired glucose tolerance (= gestational pre-diabetes).

Not only was there a positive association between the DNA methylation levels of the offspring’s leptin gene (measured in the placenta) and the glucose response to an oral glucose test, but there was also a negative relationship to placental leptin gene expression.

DNA methylation is a form of “epigenetic” modification that determines the extent to which a given gene is expressed in vivo. Thus although the genetic code or DNA sequence for that gene may be identical between two individuals, variations in DNA methylation will determine how “active” this gene is in a given individual.

The authors conclude that impaired glucose tolerance during pregnancy is associated with epigentic modification of the leptin gene with potential functional impacts that could in part account for the detrimental health effects associated with fetal programming such as long-term increased risk of developing obesity and type 2 diabetes.

As I have noted before, obesity may well start in the womb, which is why recent recommendations have focussed on improving maternal health, including the prevention of excess weight gain during pregnancy, as a key strategy to reduce childhood obesity.

AMS
Edmonton, Alberta

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Bouchard L, Thibault S, Guay SP, Santure M, Monpetit A, St-Pierre J, Perron P, & Brisson D (2010). Leptin Gene Epigenetic Adaptation to Impaired Glucose Metabolism during Pregnancy. Diabetes care PMID: 20724651

While the phenomenon of depression during and following pregnancy in women is widely appreciated (and often associated with weight gain and/or antenatal weight retention), the effect of pregnancy on mood of fathers is less appreciated.

A recent study by James Paulson and Sharnail Bazemore from the Virginia Medical School, Norfolk, VA, just published in the Journal of the American Medical Association, throws new light on this interesting issue.

The researchers performed a meta-analysis of 43 studies that documented depression in fathers between the first trimester and the first postpartum year involving 28 004 participant.

Although there was substantial heterogeneity between the rates of paternal depression between studies, the average rate of paternal depression in the antenatal period (during pregnancy) was abour 10% but increased to about 25% during the 3 to 6-month postpartum period (after birth).

While paternal depression was more likely in the presence of maternal depression, this was by no means a strong predictor of paternal mood disorder.

These findings have important implications.

Not only is it important to also be wary of mood disorders in expecting and new fathers (especially if the mother has mood problems), but these mood disorders in fathers may need to be addressed.

This is of particular importance given the emerging evidence that paternal depression may have substantial emotional, behavioural and developmental effects on the infant.

Furthermore, it may well be that paternal peripartum depression could contribute to weight gain in dads.

Thus, prevention, screening and interventions for depression should likely be focussed on the couple rather than on the individual parent.

AMS
Oslo, Norway

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Paulson JF, & Bazemore SD (2010). Prenatal and postpartum depression in fathers and its association with maternal depression: a meta-analysis. JAMA : the journal of the American Medical Association, 303 (19), 1961-9 PMID: 20483973

Yesterday, at the Second Canadian Student Obesity meeting, currently being held in Ottawa, Kristi Adamo from the University of Ottawa and the Children’s Hospital of Eastern Ontario presented the Keynote dinner presentation on “Balancing Work and Life on the Pathway of a Research Scientist“.

Kristi Adamo has a background in nutrition, exercise physiology and genetics of obesity. Her interests lie in the irregular metabolic function associated with childhood obesity and the role diet and exercise may play in predisposition or prevention. She has particular interest in early intervention to prevent child obesity and is focusing on intervening during the gestational period and halting the intergenerational cycle of obesity.

In fact, several of the presentations at this meeting emphasized the fascinating biology of how early fetal development and influences in the first weeks and months after birth can change the lifelong risk for obesity by changing how genes are switched on or off through mechanisms like imprinting and how maternal and environmental influences during this critical period can change how the complex circuitry of appetite and reward are “hardwired” into the brain.

Thus for e.g., Lindsay Naef from McGill University talked about her experiments in rats showing that exposure to high-fat diets during early development results in increased reward value of fatty foods in adult animals or Christian Rueda-Clausen from the University of Alberta, who talked about how intrauterine growth restriction increases the susceptibility to diet-induced obesity and insulin resistance.

For this very reason, other presentations examined interventions to improve diet and physical activity during pregnancy with a focus on limiting weight gain to the levels recommended by the Institute of Medicine and other organisations. As pointed out by Zach Ferraro (one of the student organisers from the University of Ottawa), not only do mothers with overweight and obesity end up gaining far more than the recommended amount of weight during gestation, but that this is also associated with an almost 6-fold higher risk of having a “supersized” baby that will eventually grow into a “supersized” adult.

So while Adamo spoke about her own pursuit of work-life balance by focussing on what she loves doing, she noted that as a mother, her professional interest on the environmental impact of fetal and early postnatal development is quite complementary to her personal goal of raising her own children in the most healthy way possible.

AMS
Ottawa, Ontario

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Walker CD, Naef L, d’Asti E, Long H, Xu Z, Moreau A, & Azeddine B (2008). Perinatal maternal fat intake affects metabolism and hippocampal function in the offspring: a potential role for leptin. Annals of the New York Academy of Sciences, 1144, 189-202 PMID: 19076377